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1. Evidence for a pathogenic role of extrafollicular, IL-10–producing CCR6⁺B helper T cells in systemic lupus erythematosus

Author

Facciotti, F., Larghi, P., Bosotti, R., Vasco, C., Gagliani, N., Cordiglierif, C., Mazzarag, S., Ranzani, V., Rottoli, E., Curti, S., Penatti, A., Karnani, B., Kobayashi, Y., Crosti, M., Bombaci, M., van Hamburg, J. P., Rossetti, G., Gualtierotti, R., Gerosa, M., Gatti, S., Torretta, S., Pignataro, L., Tas, S. W., Abrignani, S., Pagani, M., Grassi, F., Meroni, P. L., Flavell, R. A., and Geginat, J.

Published
2020

2. Regulatory T-cell-derived interleukin-15 shapes cytotoxic T cell memory

Author

Geginat, J, Granucci, F, Geginat J., Granucci F., Geginat, J, Granucci, F, Geginat J., and Granucci F.

Abstract

It is well known that regulatory T-cells (Tregs) are required to prevent autoimmunity, but they may also have some less-well understood immune-stimulatory effects. In particular, in CD8(+) T-cell responses Tregs select high-affinity clones upon priming and promote memory by inhibiting inflammation-dependent generation of short-lived effector cells. In the current issue of the European Journal of Immunology [Eur. J. Immunol. 2023. 53: XXXX-XXXX], Madi et al. report the surprising finding that human and murine FOXP3(+) Tregs are a physiologically relevant source of IL-15, a homeostatic cytokine that promotes antigen-independent maintenance of CD8(+) memory T-cells. In mice that lack IL-15 selectively in FOXP3(+)Tregs the authors show that the composition of the CD8(+) T-cell memory pool is altered in the absence of Treg-derived IL-15, since a subset of terminally effector memory cells is drastically reduced. Otherwise Treg-derived IL-15 is dispensable for antiviral immune responses and the generation of anti-viral CD8(+) memory T-cells. These findings add to our understanding of the multifaceted role of Tregs in immune responses, and how IL-15 derived from different cellular sources maintains anti-viral T-cell memory.

Published
2023

5. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

Author

Cossarizza, A, Chang, H, Radbruch, A, Abrignani, S, Addo, R, Akdis, M, Andra, I, Andreata, F, Annunziato, F, Arranz, E, Bacher, P, Bari, S, Barnaba, V, Barros-Martins, J, Baumjohann, D, Beccaria, C, Bernardo, D, Boardman, D, Borger, J, Bottcher, C, Brockmann, L, Burns, M, Busch, D, Cameron, G, Cammarata, I, Cassotta, A, Chang, Y, Chirdo, F, Christakou, E, Cicin-Sain, L, Cook, L, Corbett, A, Cornelis, R, Cosmi, L, Davey, M, De Biasi, S, De Simone, G, del Zotto, G, Delacher, M, Di Rosa, F, Santo, J, Diefenbach, A, Dong, J, Dorner, T, Dress, R, Dutertre, C, Eckle, S, Eede, P, Evrard, M, Falk, C, Feuerer, M, Fillatreau, S, Fiz-Lopez, A, Follo, M, Foulds, G, Frobel, J, Gagliani, N, Galletti, G, Gangaev, A, Garbi, N, Garrote, J, Geginat, J, Gherardin, N, Gibellini, L, Ginhoux, F, Godfrey, D, Gruarin, P, Haftmann, C, Hansmann, L, Harpur, C, Hayday, A, Heine, G, Hernandez, D, Herrmann, M, Hoelsken, O, Huang, Q, Huber, S, Huber, J, Huehn, J, Hundemer, M, Hwang, W, Iannacone, M, Ivison, S, Jack, H, Jani, P, Keller, B, Kessler, N, Ketelaars, S, Knop, L, Knopf, J, Koay, H, Kobow, K, Kriegsmann, K, Kristyanto, H, Krueger, A, Kuehne, J, Kunze-Schumacher, H, Kvistborg, P, Kwok, I, Latorre, D, Lenz, D, Levings, M, Lino, A, Liotta, F, Long, H, Lugli, E, Macdonald, K, Maggi, L, Maini, M, Mair, F, Manta, C, Manz, R, Mashreghi, M, Mazzoni, A, Mccluskey, J, Mei, H, Melchers, F, Melzer, S, Mielenz, D, Monin, L, Moretta, L, Multhoff, G, Munoz, L, Munoz-Ruiz, M, Muscate, F, Natalini, A, Neumann, K, Ng, L, Niedobitek, A, Niemz, J, Almeida, L, Notarbartolo, S, Ostendorf, L, Pallett, L, Patel, A, Percin, G, Peruzzi, G, Pinti, M, Pockley, A, Pracht, K, Prinz, I, Pujol-Autonell, I, Pulvirenti, N, Quatrini, L, Quinn, K, Radbruch, H, Rhys, H, Rodrigo, M, Romagnani, C, Saggau, C, Sakaguchi, S, Sallusto, F, Sanderink, L, Sandrock, I, Schauer, C, Scheffold, A, Scherer, H, Schiemann, M, Schildberg, F, Schober, K, Schoen, J, Schuh, W, Schuler, T, Schulz, A, Schulz, S, Schulze, J, Simonetti, S, Singh, J, Sitnik, K, Stark, R, Starossom, S, Stehle, C, Szelinski, F, Tan, L, Tarnok, A, Tornack, J, Tree, T, van Beek, J, van de Veen, W, van Gisbergen, K, Vasco, C, Verheyden, N, von Borstel, A, Ward-Hartstonge, K, Warnatz, K, Waskow, C, Wiedemann, A, Wilharm, A, Wing, J, Wirz, O, Wittner, J, Yang, J, Cossarizza A., Chang H. -D., Radbruch A., Abrignani S., Addo R., Akdis M., Andra I., Andreata F., Annunziato F., Arranz E., Bacher P., Bari S., Barnaba V., Barros-Martins J., Baumjohann D., Beccaria C. G., Bernardo D., Boardman D. A., Borger J., Bottcher C., Brockmann L., Burns M., Busch D. H., Cameron G., Cammarata I., Cassotta A., Chang Y., Chirdo F. G., Christakou E., Cicin-Sain L., Cook L., Corbett A. J., Cornelis R., Cosmi L., Davey M. S., De Biasi S., De Simone G., del Zotto G., Delacher M., Di Rosa F., Santo J. D., Diefenbach A., Dong J., Dorner T., Dress R. J., Dutertre C. -A., Eckle S. B. G., Eede P., Evrard M., Falk C. S., Feuerer M., Fillatreau S., Fiz-Lopez A., Follo M., Foulds G. A., Frobel J., Gagliani N., Galletti G., Gangaev A., Garbi N., Garrote J. A., Geginat J., Gherardin N. A., Gibellini L., Ginhoux F., Godfrey D. I., Gruarin P., Haftmann C., Hansmann L., Harpur C. M., Hayday A. C., Heine G., Hernandez D. C., Herrmann M., Hoelsken O., Huang Q., Huber S., Huber J. E., Huehn J., Hundemer M., Hwang W. Y. K., Iannacone M., Ivison S. M., Jack H. -M., Jani P. K., Keller B., Kessler N., Ketelaars S., Knop L., Knopf J., Koay H. -F., Kobow K., Kriegsmann K., Kristyanto H., Krueger A., Kuehne J. F., Kunze-Schumacher H., Kvistborg P., Kwok I., Latorre D., Lenz D., Levings M. K., Lino A. C., Liotta F., Long H. M., Lugli E., MacDonald K. N., Maggi L., Maini M. K., Mair F., Manta C., Manz R. A., Mashreghi M. -F., Mazzoni A., McCluskey J., Mei H. E., Melchers F., Melzer S., Mielenz D., Monin L., Moretta L., Multhoff G., Munoz L. E., Munoz-Ruiz M., Muscate F., Natalini A., Neumann K., Ng L. G., Niedobitek A., Niemz J., Almeida L. N., Notarbartolo S., Ostendorf L., Pallett L. J., Patel A. A., Percin G. I., Peruzzi G., Pinti M., Pockley A. G., Pracht K., Prinz I., Pujol-Autonell I., Pulvirenti N., Quatrini L., Quinn K. M., Radbruch H., Rhys H., Rodrigo M. B., Romagnani C., Saggau C., Sakaguchi S., Sallusto F., Sanderink L., Sandrock I., Schauer C., Scheffold A., Scherer H. U., Schiemann M., Schildberg F. A., Schober K., Schoen J., Schuh W., Schuler T., Schulz A. R., Schulz S., Schulze J., Simonetti S., Singh J., Sitnik K. M., Stark R., Starossom S., Stehle C., Szelinski F., Tan L., Tarnok A., Tornack J., Tree T. I. M., van Beek J. J. P., van de Veen W., van Gisbergen K., Vasco C., Verheyden N. A., von Borstel A., Ward-Hartstonge K. A., Warnatz K., Waskow C., Wiedemann A., Wilharm A., Wing J., Wirz O., Wittner J., Yang J. H. M., Yang J., Cossarizza, A, Chang, H, Radbruch, A, Abrignani, S, Addo, R, Akdis, M, Andra, I, Andreata, F, Annunziato, F, Arranz, E, Bacher, P, Bari, S, Barnaba, V, Barros-Martins, J, Baumjohann, D, Beccaria, C, Bernardo, D, Boardman, D, Borger, J, Bottcher, C, Brockmann, L, Burns, M, Busch, D, Cameron, G, Cammarata, I, Cassotta, A, Chang, Y, Chirdo, F, Christakou, E, Cicin-Sain, L, Cook, L, Corbett, A, Cornelis, R, Cosmi, L, Davey, M, De Biasi, S, De Simone, G, del Zotto, G, Delacher, M, Di Rosa, F, Santo, J, Diefenbach, A, Dong, J, Dorner, T, Dress, R, Dutertre, C, Eckle, S, Eede, P, Evrard, M, Falk, C, Feuerer, M, Fillatreau, S, Fiz-Lopez, A, Follo, M, Foulds, G, Frobel, J, Gagliani, N, Galletti, G, Gangaev, A, Garbi, N, Garrote, J, Geginat, J, Gherardin, N, Gibellini, L, Ginhoux, F, Godfrey, D, Gruarin, P, Haftmann, C, Hansmann, L, Harpur, C, Hayday, A, Heine, G, Hernandez, D, Herrmann, M, Hoelsken, O, Huang, Q, Huber, S, Huber, J, Huehn, J, Hundemer, M, Hwang, W, Iannacone, M, Ivison, S, Jack, H, Jani, P, Keller, B, Kessler, N, Ketelaars, S, Knop, L, Knopf, J, Koay, H, Kobow, K, Kriegsmann, K, Kristyanto, H, Krueger, A, Kuehne, J, Kunze-Schumacher, H, Kvistborg, P, Kwok, I, Latorre, D, Lenz, D, Levings, M, Lino, A, Liotta, F, Long, H, Lugli, E, Macdonald, K, Maggi, L, Maini, M, Mair, F, Manta, C, Manz, R, Mashreghi, M, Mazzoni, A, Mccluskey, J, Mei, H, Melchers, F, Melzer, S, Mielenz, D, Monin, L, Moretta, L, Multhoff, G, Munoz, L, Munoz-Ruiz, M, Muscate, F, Natalini, A, Neumann, K, Ng, L, Niedobitek, A, Niemz, J, Almeida, L, Notarbartolo, S, Ostendorf, L, Pallett, L, Patel, A, Percin, G, Peruzzi, G, Pinti, M, Pockley, A, Pracht, K, Prinz, I, Pujol-Autonell, I, Pulvirenti, N, Quatrini, L, Quinn, K, Radbruch, H, Rhys, H, Rodrigo, M, Romagnani, C, Saggau, C, Sakaguchi, S, Sallusto, F, Sanderink, L, Sandrock, I, Schauer, C, Scheffold, A, Scherer, H, Schiemann, M, Schildberg, F, Schober, K, Schoen, J, Schuh, W, Schuler, T, Schulz, A, Schulz, S, Schulze, J, Simonetti, S, Singh, J, Sitnik, K, Stark, R, Starossom, S, Stehle, C, Szelinski, F, Tan, L, Tarnok, A, Tornack, J, Tree, T, van Beek, J, van de Veen, W, van Gisbergen, K, Vasco, C, Verheyden, N, von Borstel, A, Ward-Hartstonge, K, Warnatz, K, Waskow, C, Wiedemann, A, Wilharm, A, Wing, J, Wirz, O, Wittner, J, Yang, J, Cossarizza A., Chang H. -D., Radbruch A., Abrignani S., Addo R., Akdis M., Andra I., Andreata F., Annunziato F., Arranz E., Bacher P., Bari S., Barnaba V., Barros-Martins J., Baumjohann D., Beccaria C. G., Bernardo D., Boardman D. A., Borger J., Bottcher C., Brockmann L., Burns M., Busch D. H., Cameron G., Cammarata I., Cassotta A., Chang Y., Chirdo F. G., Christakou E., Cicin-Sain L., Cook L., Corbett A. J., Cornelis R., Cosmi L., Davey M. S., De Biasi S., De Simone G., del Zotto G., Delacher M., Di Rosa F., Santo J. D., Diefenbach A., Dong J., Dorner T., Dress R. J., Dutertre C. -A., Eckle S. B. G., Eede P., Evrard M., Falk C. S., Feuerer M., Fillatreau S., Fiz-Lopez A., Follo M., Foulds G. A., Frobel J., Gagliani N., Galletti G., Gangaev A., Garbi N., Garrote J. A., Geginat J., Gherardin N. A., Gibellini L., Ginhoux F., Godfrey D. I., Gruarin P., Haftmann C., Hansmann L., Harpur C. M., Hayday A. C., Heine G., Hernandez D. C., Herrmann M., Hoelsken O., Huang Q., Huber S., Huber J. E., Huehn J., Hundemer M., Hwang W. Y. K., Iannacone M., Ivison S. M., Jack H. -M., Jani P. K., Keller B., Kessler N., Ketelaars S., Knop L., Knopf J., Koay H. -F., Kobow K., Kriegsmann K., Kristyanto H., Krueger A., Kuehne J. F., Kunze-Schumacher H., Kvistborg P., Kwok I., Latorre D., Lenz D., Levings M. K., Lino A. C., Liotta F., Long H. M., Lugli E., MacDonald K. N., Maggi L., Maini M. K., Mair F., Manta C., Manz R. A., Mashreghi M. -F., Mazzoni A., McCluskey J., Mei H. E., Melchers F., Melzer S., Mielenz D., Monin L., Moretta L., Multhoff G., Munoz L. E., Munoz-Ruiz M., Muscate F., Natalini A., Neumann K., Ng L. G., Niedobitek A., Niemz J., Almeida L. N., Notarbartolo S., Ostendorf L., Pallett L. J., Patel A. A., Percin G. I., Peruzzi G., Pinti M., Pockley A. G., Pracht K., Prinz I., Pujol-Autonell I., Pulvirenti N., Quatrini L., Quinn K. M., Radbruch H., Rhys H., Rodrigo M. B., Romagnani C., Saggau C., Sakaguchi S., Sallusto F., Sanderink L., Sandrock I., Schauer C., Scheffold A., Scherer H. U., Schiemann M., Schildberg F. A., Schober K., Schoen J., Schuh W., Schuler T., Schulz A. R., Schulz S., Schulze J., Simonetti S., Singh J., Sitnik K. M., Stark R., Starossom S., Stehle C., Szelinski F., Tan L., Tarnok A., Tornack J., Tree T. I. M., van Beek J. J. P., van de Veen W., van Gisbergen K., Vasco C., Verheyden N. A., von Borstel A., Ward-Hartstonge K. A., Warnatz K., Waskow C., Wiedemann A., Wilharm A., Wing J., Wirz O., Wittner J., Yang J. H. M., and Yang J.

Abstract

The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers.

Published
2021

6. Ex vivo microRNA and gene expression profiling of human Tr1-like cells suggests a role for miR-92a and -125a in the regulation of EOMES and IL-10R

Author

De Simone, M, Chirichella, M, Emming, S, Mazzara, S, Ranzani, V, Gruarin, P, Moschetti, G, Pulvirenti, N, Maglie, S, Vasco, C, Crosti, M, Rossetti, G, Pagani, M, Abrignani, S, Monticelli, S, Geginat, J, De Simone M., Chirichella M., Emming S., Mazzara S., Ranzani V., Gruarin P., Moschetti G., Pulvirenti N., Maglie S., Vasco C., Crosti M. C., Rossetti G., Pagani M., Abrignani S., Monticelli S., Geginat J., De Simone, M, Chirichella, M, Emming, S, Mazzara, S, Ranzani, V, Gruarin, P, Moschetti, G, Pulvirenti, N, Maglie, S, Vasco, C, Crosti, M, Rossetti, G, Pagani, M, Abrignani, S, Monticelli, S, Geginat, J, De Simone M., Chirichella M., Emming S., Mazzara S., Ranzani V., Gruarin P., Moschetti G., Pulvirenti N., Maglie S., Vasco C., Crosti M. C., Rossetti G., Pagani M., Abrignani S., Monticelli S., and Geginat J.

Abstract

Ex vivo gene expression and miRNA profiling of Eomes+ Tr1-like cells suggested that they represent a differentiation stage that is intermediate between Th1-cells and cytotoxic CD4+ T-cells. Several microRNAs were downregulated in Eomes+ Tr1-like cells that might inhibit Tr1-cell differentiation. In particular, miR-92a targeted Eomes, while miR-125a inhibited IFN-g and IL-10R expression.

Published
2021

7. Evidence for a pathogenic role of extrafollicular, IL-10-producing CCR6+B helper T cells in systemic lupus erythematosus

Author

Facciotti, F, Larghi, P, Bosotti, R, Vasco, C, Gagliani, N, Cordiglieri, C, Mazzara, S, Ranzani, V, Rottoli, E, Curti, S, Penatti, A, Karnani, B, Kobayashi, Y, Crosti, M, Bombaci, M, van Hamburg, J, Rossetti, G, Gualtierotti, R, Gerosa, M, Gatti, S, Torretta, S, Pignataro, L, Tas, S, Abrignani, S, Pagani, M, Grassi, F, Meroni, P, Flavell, R, Geginat, J, Facciotti F, Larghi P, Bosotti R, Vasco C, Gagliani N, Cordiglieri C, Mazzara S, Ranzani V, Rottoli E, Curti S, Penatti A, Karnani B, Kobayashi Y, Crosti M, Bombaci M, van Hamburg JP, Rossetti G, Gualtierotti R, Gerosa M, Gatti S, Torretta S, Pignataro L, Tas SW, Abrignani S, Pagani M, Grassi F, Meroni PL, Flavell RA, Geginat J, Facciotti, F, Larghi, P, Bosotti, R, Vasco, C, Gagliani, N, Cordiglieri, C, Mazzara, S, Ranzani, V, Rottoli, E, Curti, S, Penatti, A, Karnani, B, Kobayashi, Y, Crosti, M, Bombaci, M, van Hamburg, J, Rossetti, G, Gualtierotti, R, Gerosa, M, Gatti, S, Torretta, S, Pignataro, L, Tas, S, Abrignani, S, Pagani, M, Grassi, F, Meroni, P, Flavell, R, Geginat, J, Facciotti F, Larghi P, Bosotti R, Vasco C, Gagliani N, Cordiglieri C, Mazzara S, Ranzani V, Rottoli E, Curti S, Penatti A, Karnani B, Kobayashi Y, Crosti M, Bombaci M, van Hamburg JP, Rossetti G, Gualtierotti R, Gerosa M, Gatti S, Torretta S, Pignataro L, Tas SW, Abrignani S, Pagani M, Grassi F, Meroni PL, Flavell RA, and Geginat J

Abstract

Interleukin 10 (IL-10) is an antiinflammatory cytokine, but also promotes B cell responses and plays a pathogenic role in systemic lupus erythematosus (SLE). CD4+CCR6+IL-7R+T cells from human tonsils produced IL-10 following stimulation by naïve B cells, which promoted B cell immunoglobulin G (IgG) production. These tonsillar CCR6+B helper T cells were phenotypically distinct from follicular helper T (TFH) cells and lacked BCL6 expression. In peripheral blood, a CCR6+T cell population with similar characteristics was identified, which lacked Th17- and TFH-associated gene signatures and differentiation-associated surface markers. CD4+CCR6+T cells expressing IL-10, but not IL-17, were also detectable in the spleens of cytokine reporter mice. They provided help for IgG production in vivo, and expanded systemically in pristane-induced lupus-like disease. In SLE patients, CD4+CCR6+IL-7R+T cells were associated with the presence of pathogenic anti-dsDNA (doublestranded DNA) antibodies, and provided spontaneous help for autoantibody production ex vivo. Strikingly, IL-10-producing CCR6+T cells were highly abundant in lymph nodes of SLE patients, and colocalized with B cells at the margins of follicles. In conclusion, we identified a previously uncharacterized population of extrafollicular B helper T cells, which produced IL-10 and could play a prominent pathogenic role in SLE.

Published
2020

8. Functional Subsets of Memory T Cells Identified by CCR7 Expression

Author

Sallusto, F., Langenkamp, A., Geginat, J., Lanzavecchia, A., Compans, R. W., editor, Cooper, M., editor, Hogle, J. M., editor, Ito, Y., editor, Koprowski, H., editor, Melchers, F., editor, Oldstone, M., editor, Olsnes, S., editor, Potter, M., editor, Saedler, H., editor, Vogt, P. K., editor, Wagner, H., editor, and Melchers, Fritz, editor

Published
2000
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10. Eomesodermin controls a unique differentiation program in human IL-10 and IFN-gamma coproducing regulatory T cells

Author

Gruarin, P, Maglie, S, De Simone, M, Haringer, B, Vasco, C, Ranzani, V, Bosotti, R, Noddings, J, Larghi, P, Facciotti, F, Sarnicola, M, Martinovic, M, Crosti, M, Moro, M, Rossi, R, Bernardo, M, Caprioli, F, Locatelli, F, Rossetti, G, Abrignani, S, Pagani, M, Geginat, J, Gruarin P, Maglie S, De Simone M, Haringer B, Vasco C, Ranzani V, Bosotti R, Noddings JS, Larghi P, Facciotti F, Sarnicola ML, Martinovic M, Crosti M, Moro M, Rossi RL, Bernardo ME, Caprioli F, Locatelli F, Rossetti G, Abrignani S, Pagani M, Geginat J, Gruarin, P, Maglie, S, De Simone, M, Haringer, B, Vasco, C, Ranzani, V, Bosotti, R, Noddings, J, Larghi, P, Facciotti, F, Sarnicola, M, Martinovic, M, Crosti, M, Moro, M, Rossi, R, Bernardo, M, Caprioli, F, Locatelli, F, Rossetti, G, Abrignani, S, Pagani, M, Geginat, J, Gruarin P, Maglie S, De Simone M, Haringer B, Vasco C, Ranzani V, Bosotti R, Noddings JS, Larghi P, Facciotti F, Sarnicola ML, Martinovic M, Crosti M, Moro M, Rossi RL, Bernardo ME, Caprioli F, Locatelli F, Rossetti G, Abrignani S, Pagani M, and Geginat J

Abstract

Whether human IL-10-producing regulatory T cells ("Tr1") represent a distinct differentiation lineage or an unstable activation stage remains a key unsolved issue. Here, we report that Eomesodermin (Eomes) acted as a lineage-defining transcription factor in human IFN-gamma/IL-10 coproducing Tr1-like cells. In vivo occurring Tr1-like cells expressed Eomes, and were clearly distinct from all other CD4(+) T-cell subsets, including conventional cytotoxic CD4(+) T cells. They expressed Granzyme (Gzm) K, but had lost CD40L and IL-7R expression. Eomes antagonized the Th17 fate, and directly controlled IFN-gamma and GzmK expression. However, Eomes binding to the IL-10 promoter was not detectable in human CD4(+) T cells, presumably because critical Tbox binding sites of the mouse were not conserved. A precommitment to a Tr1-like fate, i.e. concominant induction of Eomes, GzmK, and IFN-gamma, was promoted by IL-4 and IL-12-secreting myeloid dendritic cells. Consistently, Th1 effector memory cells contained precommitted Eomes(+)GzmK(+) T cells. Stimulation with T-cell receptor (TCR) agonists and IL-27 promoted the generation of Tr1-like effector cells by inducing switching from CD40L to IL-10. Importantly, CD4(+)Eomes(+) T-cell subsets were present in lymphoid and nonlymphoid tissues, and their frequencies varied systemically in patients with inflammatory bowel disease and graft-versus-host disease. We propose that Eomes(+) Tr1-like cells are effector cells of a unique GzmK-expressing CD4(+) T-cell subset.

Published
2019

11. Novel biomarkers for primary biliary cholangitis to improve diagnosis and understand underlying regulatory mechanisms

Author

Bombaci, M, Pesce, E, Torri, A, Carpi, D, Crosti, M, Lanzafame, M, Cordiglieri, C, Sinisi, A, DEL MORO, L, Bernuzzi, F, Gerussi, A, Geginat, J, Muratori, L, Terracciano, L, Invernizzi, P, Abrignani, S, Grifantini, R, Bombaci M., Pesce E., Torri A., Carpi D., Crosti M., Lanzafame M., Cordiglieri C., Sinisi A., DEL MORO, LILIA ANNA PAOLA MARIA, Bernuzzi F., Gerussi A., Geginat J., Muratori L., Terracciano L. M., Invernizzi P., Abrignani S., Grifantini R., Bombaci, M, Pesce, E, Torri, A, Carpi, D, Crosti, M, Lanzafame, M, Cordiglieri, C, Sinisi, A, DEL MORO, L, Bernuzzi, F, Gerussi, A, Geginat, J, Muratori, L, Terracciano, L, Invernizzi, P, Abrignani, S, Grifantini, R, Bombaci M., Pesce E., Torri A., Carpi D., Crosti M., Lanzafame M., Cordiglieri C., Sinisi A., DEL MORO, LILIA ANNA PAOLA MARIA, Bernuzzi F., Gerussi A., Geginat J., Muratori L., Terracciano L. M., Invernizzi P., Abrignani S., and Grifantini R.

Abstract

Background and aims: Primary biliary cholangitis is an autoimmune biliary disease characterized by injury of bile ducts, eventually leading to cirrhosis and death. In most cases, anti-mitochondrial antibodies and persistently elevated serum alkaline phosphatase are the basis for the serological diagnosis. Anti-nuclear antibodies are also useful and may indicate a more aggressive diseases course. In patients in which anti-mitochondrial antibodies are not detected, an accurate diagnosis requires liver histology. This study aims at identifying specific biomarkers for the serological diagnosis of primary biliary cholangitis. Methods: Sera from patients affected by primary biliary cholangitis, primary sclerosing cholangitis, hepatitis C virus (with and without cryoglobulinemia), hepatocarcinoma and healthy donors were tested on a protein array representing 1658 human proteins. The most reactive autoantigens were confirmed by DELFIA analysis on expanded cohorts of the same mentioned serum classes, and on autoimmune hepatitis sera, using anti-PDC-E2 as reference biomarker. Results: Two autoantigens, SPATA31A3 and GARP, showed high reactivity with primary biliary cholangitis sera, containing or not anti-mitochondrial antibodies. Their combination with PDC-E2 allowed to discriminate primary biliary cholangitis from all tested control classes with high sensitivity and specificity. We found that GARP expression is upregulated upon exposure to biliary salts in human cholangiocytes, an event involving EGFR and insulin pathways. GARP expression was also detected in biliary duct cells of PBC patients. Conclusions: This study highlighted SPATA31A3 and GARP as new biomarkers for primary biliary cholangitis and unravelled molecular stimuli underlying GARP expression in human cholangiocytes

Published
2019

12. Clonally expanded EOMES+ Tr1-like cells in primary and metastatic tumors are associated with disease progression

Author

Bonnal, R.J., Rossetti, G., Lugli, E., Simone, M. De, Gruarin, P., Brummelman, J., Drufuca, L., Passaro, M., Bason, R., Gervasoni, F., Chiara, G. Della, D'Oria, C., Martinovic, M., Curti, S., Ranzani, V., Cordiglieri, C., Alvisi, G., Mazza, E.M.C., Oliveto, S., Silvestri, Y., Carelli, E., Mazzara, S., Bosotti, R., Sarnicola, M.L., Godano, C., Bevilacqua, V., Lorenzo, M., Siena, S. Di, Bonoldi, E., Sartore-Bianchi, A., Amatu, A., Veronesi, G., Novellis, P., Alloisio, M., Giani, A., Zucchini, N., Opocher, E., Ceretti, A.P., Mariani, N., Biffo, S., Prati, D., Bardelli, A., Geginat, J., Lanzavecchia, A., Abrignani, S., Pagani, M., Bonnal, R.J., Rossetti, G., Lugli, E., Simone, M. De, Gruarin, P., Brummelman, J., Drufuca, L., Passaro, M., Bason, R., Gervasoni, F., Chiara, G. Della, D'Oria, C., Martinovic, M., Curti, S., Ranzani, V., Cordiglieri, C., Alvisi, G., Mazza, E.M.C., Oliveto, S., Silvestri, Y., Carelli, E., Mazzara, S., Bosotti, R., Sarnicola, M.L., Godano, C., Bevilacqua, V., Lorenzo, M., Siena, S. Di, Bonoldi, E., Sartore-Bianchi, A., Amatu, A., Veronesi, G., Novellis, P., Alloisio, M., Giani, A., Zucchini, N., Opocher, E., Ceretti, A.P., Mariani, N., Biffo, S., Prati, D., Bardelli, A., Geginat, J., Lanzavecchia, A., Abrignani, S., and Pagani, M.

Abstract

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Published
2021

13. Intestinal IFN-gamma-producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease

Author

Alfen, J, Larghi, P, Facciotti, F, Gagliani, N, Bosotti, R, Paroni, M, Maglie, S, Gruarin, P, Vasco, C, Ranzani, V, Frusteri, C, Iseppon, A, Moro, M, Crosti, M, Gatti, S, Pagani, M, Caprioli, F, Abrignani, S, Flavell, R, Geginat, J, Alfen JS, Larghi P, Facciotti F, Gagliani N, Bosotti R, Paroni M, Maglie S, Gruarin P, Vasco CM, Ranzani V, Frusteri C, Iseppon A, Moro M, Crosti MC, Gatti S, Pagani M, Caprioli F, Abrignani S, Flavell RA, Geginat J, Alfen, J, Larghi, P, Facciotti, F, Gagliani, N, Bosotti, R, Paroni, M, Maglie, S, Gruarin, P, Vasco, C, Ranzani, V, Frusteri, C, Iseppon, A, Moro, M, Crosti, M, Gatti, S, Pagani, M, Caprioli, F, Abrignani, S, Flavell, R, Geginat, J, Alfen JS, Larghi P, Facciotti F, Gagliani N, Bosotti R, Paroni M, Maglie S, Gruarin P, Vasco CM, Ranzani V, Frusteri C, Iseppon A, Moro M, Crosti MC, Gatti S, Pagani M, Caprioli F, Abrignani S, Flavell RA, and Geginat J

Abstract

Background: IL-10 is an anti-inflammatory cytokine required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type 1 regulatory T (T(R)1) cells but is also produced by CD25(+) regulatory T (Treg) cells. Objective: We aimed to identify and characterize human intestinal T(R)1 cells and to investigate whether they are a relevant cellular source of IL-10 in patients with inflammatory bowel diseases (IBDs). Methods: CD4(+) T cells isolated from the intestinal lamina propria of human subjects and mice were analyzed for phenotype, cytokine production, and suppressive capacities. Intracellular IL-10 expression by CD4(+) T-cell subsets in the inflamed guts of patients with IBD (Crohn disease or ulcerative colitis) was compared with that in cells from noninflamed control subjects. Finally, the effects of proinflammatory cytokines on T-cell IL-10 expression were analyzed, and IL-1 beta and IL-23 responsiveness was assessed. Results: Intestinal T(R)1 cells could be identified by coexpression of CCR5 and programmed cell death protein 1 (PD-1) in human subjects and mice. CCR5(+) PD-1(+) T(R)1 cells expressed IFN-gamma and efficiently suppressed T-cell proliferation and transfer colitis. Intestinal IFN-gamma(+) T(R)1 cells, but not IL-7 receptor-positive T-H cells or CD25(+) Treg cells, showed lower IL-10 expression in patients with IBDs. T(R)1 cells were responsive to IL-23, and IFN-gamma(+) T(R)1 cells downregulated IL-10 with IL-1 beta and IL-23. Conversely, CD25(+) Treg cells expressed higher levels of IL-1 receptor but showed stable IL-10 expression. Conclusions: We provide the first ex vivo characterization of human intestinal T(R)1 cells. Selective downregulation of IL-10 by IFN-gamma(+) T(R)1 cells in response to proinflammatory cytokines is likely to drive excessive intestinal inflammation in patients with IBDs.

Published
2018

14. The induction and function of the anti-inflammatory fate of T H 17 cells

Author

Xu H, Agalioti T, Zhao J, Steglich B, Wahib R, Vesely MCA, Bielecki P, Bailis W, Jackson R, Perez D, Izbicki J, Licona-Limón P, Kaartinen V, Geginat J, Esplugues E, Tolosa E, Huber S, Flavell RA, and Gagliani N

Abstract

T H 17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of T H 17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-ß signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in T H 17 cells. Our data thus indicate a key function of T H 17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of T H 17 cells with regard to environmental changes.

Published
2020

15. THU0221 EVIDENCE FOR A PATHOGENIC ROLE OF EXTRA-FOLLICULAR, IL-10 PRODUCING CCR6+B-HELPER T-CELLS IN SYSTEMIC LUPUS ERYTHEMATOSUS

Author

Gerosa, M., primary, Facciotti, F., additional, Larghi, P., additional, Bosotti, R., additional, Vasco, C., additional, Gagliani, N., additional, Cordiglieri, C., additional, Rottoli, E., additional, Penatti, A. E., additional, Argolini, L. M., additional, Karnani, B., additional, Kobayashi, Y., additional, Bombaci, M., additional, Van Hamburg, J. P., additional, Gualtierotti, R., additional, Gatti, S., additional, Torretta, S., additional, Pignataro, L., additional, Tas, S. W., additional, Caporali, R., additional, Abrignani, S., additional, Pagani, M., additional, Grassi, F., additional, Meroni, P. L., additional, Flavell, R., additional, and Geginat, J., additional

Published
2020
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16. Evidence for a pathogenic role of extrafollicular, IL-10–producing CCR6 + B helper T cells in systemic lupus erythematosus

Author

Facciotti, F., primary, Larghi, P., additional, Bosotti, R., additional, Vasco, C., additional, Gagliani, N., additional, Cordiglieri, C., additional, Mazzara, S., additional, Ranzani, V., additional, Rottoli, E., additional, Curti, S., additional, Penatti, A., additional, Karnani, B., additional, Kobayashi, Y., additional, Crosti, M., additional, Bombaci, M., additional, van Hamburg, J. P., additional, Rossetti, G., additional, Gualtierotti, R., additional, Gerosa, M., additional, Gatti, S., additional, Torretta, S., additional, Pignataro, L., additional, Tas, S. W., additional, Abrignani, S., additional, Pagani, M., additional, Grassi, F., additional, Meroni, P. L., additional, Flavell, R. A., additional, and Geginat, J., additional

Published
2020
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17. Differences in serum and synovial CD4+ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis

Author

Penatti, A, Facciotti, F, De Matteis, R, Larghi, P, Paroni, M, Murgo, A, De Lucia, O, Pagani, M, Pierannunzii, L, Truzzi, M, Ioan-Facsinay, A, Abrignani, S, Geginat, J, Meroni, P, Penatti A, Facciotti F, De Matteis R, Larghi P, Paroni M, Murgo A, De Lucia O, Pagani M, Pierannunzii L, Truzzi M, Ioan-Facsinay A, Abrignani S, Geginat J, Meroni PL., Penatti, A, Facciotti, F, De Matteis, R, Larghi, P, Paroni, M, Murgo, A, De Lucia, O, Pagani, M, Pierannunzii, L, Truzzi, M, Ioan-Facsinay, A, Abrignani, S, Geginat, J, Meroni, P, Penatti A, Facciotti F, De Matteis R, Larghi P, Paroni M, Murgo A, De Lucia O, Pagani M, Pierannunzii L, Truzzi M, Ioan-Facsinay A, Abrignani S, Geginat J, and Meroni PL.

Abstract

Background: The aim was to investigate CD4+T-cell subsets, immune cells and their cytokine profiles in blood and synovial compartments in rheumatoid arthritis (RA) and inflammatory osteoarthritis (OA) to define specific immune signatures. Methods: Peripheral blood, synovial fluid (SF) and synovial membranes (SM) of RA and OA patients were analyzed. CD4+T-cell subset frequencies were determined by flow cytometry, and cytokine concentrations in serum and SF were measured by ELISA. Results: In peripheral blood, OA patients had altered frequencies of regulatory T-cell subsets, and higher frequencies of Th17 and of Th1/17 cells than RA patients. In the synovial compartment of OA patients, conventional Th17 cells were largely excluded, while Th1/17 cells were enriched and more frequent than in RA patients. Conversely, in the synovial compartment of RA patients, regulatory T cells and Tfh cells were enriched and more frequent then in OA patients. IL-17 and Blys were increased both in serum and SF of RA patients, and correlated with autoantibodies and disease activity. Notably, Blys levels were already significantly elevated in RA patients with low disease activity score in 28 joints (DAS28) and without autoantibody positivity. Conclusions: Although patients with inflammatory OA have immune activation in the synovial compartment, they display different T-cell subset frequencies and cytokine profiles. Soluble mediators such as Blys might help to discriminate mild clinical forms of RA from inflammatory OA particularly at the onset of the disease.

Published
2017

18. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Author

Cossarizza, A, Chang, H-D, Radbruch, A, Acs, A, Adam, D, Adam-Klages, S, Agace, WW, Aghaeepour, N, Akdis, M, Allez, M, Almeida, LN, Alvisi, G, Anderson, G, Andrae, I, Annunziato, F, Anselmo, A, Bacher, P, Baldari, CT, Bari, S, Barnaba, V, Barros-Martins, J, Battistini, L, Bauer, W, Baumgart, S, Baumgarth, N, Baumjohann, D, Baying, B, Bebawy, M, Becher, B, Beisker, W, Benes, V, Beyaert, R, Blanco, A, Boardman, DA, Bogdan, C, Borger, JG, Borsellino, G, Boulais, PE, Bradford, JA, Brenner, D, Brinkman, RR, Brooks, AES, Busch, DH, Buescher, M, Bushnell, TP, Calzetti, F, Cameron, G, Cammarata, I, Cao, X, Cardell, SL, Casola, S, Cassatella, MA, Cavani, A, Celada, A, Chatenoud, L, Chattopadhyay, PK, Chow, S, Christakou, E, Cicin-Sain, L, Clerici, M, Colombo, FS, Cook, L, Cooke, A, Cooper, AM, Corbett, AJ, Cosma, A, Cosmi, L, Coulie, PG, Cumano, A, Cvetkovic, L, Dang, VD, Dang-Heine, C, Davey, MS, Davies, D, De Biasi, S, Del Zotto, G, Dela Cruz, GV, Delacher, M, Della Bella, S, Dellabona, P, Deniz, G, Dessing, M, Di Santo, JP, Diefenbach, A, Dieli, F, Dolf, A, Doerner, T, Dress, RJ, Dudziak, D, Dustin, M, Dutertre, C-A, Ebner, F, Eckle, SBG, Edinger, M, Eede, P, Ehrhardt, GRA, Eich, M, Engel, P, Engelhardt, B, Erdei, A, Esser, C, Everts, B, Evrard, M, Falk, CS, Fehniger, TA, Felipo-Benavent, M, Ferry, H, Feuerer, M, Filby, A, Filkor, K, Fillatreau, S, Follo, M, Foerster, I, Foster, J, Foulds, GA, Frehse, B, Frenette, PS, Frischbutter, S, Fritzsche, W, Galbraith, DW, Gangaev, A, Garbi, N, Gaudilliere, B, Gazzinelli, RT, Geginat, J, Gerner, W, Gherardin, NA, Ghoreschi, K, Gibellini, L, Ginhoux, F, Goda, K, Godfrey, DI, Goettlinger, C, Gonzalez-Navajas, JM, Goodyear, CS, Gori, A, Grogan, JL, Grummitt, D, Gruetzkau, A, Haftmann, C, Hahn, J, Hammad, H, Haemmerling, G, Hansmann, L, Hansson, G, Harpur, CM, Hartmann, S, Hauser, A, Hauser, AE, Haviland, DL, Hedley, D, Hernandez, DC, Herrera, G, Herrmann, M, Hess, C, Hoefer, T, Hoffmann, P, Hogquist, K, Holland, T, Hollt, T, Holmdahl, R, Hombrink, P, Houston, JP, Hoyer, BF, Huang, B, Huang, F-P, Huber, JE, Huehn, J, Hundemer, M, Hunter, CA, Hwang, WYK, Iannone, A, Ingelfinger, F, Ivison, SM, Jaeck, H-M, Jani, PK, Javega, B, Jonjic, S, Kaiser, T, Kalina, T, Kamradt, T, Kaufmann, SHE, Keller, B, Ketelaars, SLC, Khalilnezhad, A, Khan, S, Kisielow, J, Klenerman, P, Knopf, J, Koay, H-F, Kobow, K, Kolls, JK, Kong, WT, Kopf, M, Korn, T, Kriegsmann, K, Kristyanto, H, Kroneis, T, Krueger, A, Kuehne, J, Kukat, C, Kunkel, D, Kunze-Schumacher, H, Kurosaki, T, Kurts, C, Kvistborg, P, Kwok, I, Landry, J, Lantz, O, Lanuti, P, LaRosa, F, Lehuen, A, LeibundGut-Landmann, S, Leipold, MD, Leung, LYT, Levings, MK, Lino, AC, Liotta, F, Litwin, V, Liu, Y, Ljunggren, H-G, Lohoff, M, Lombardi, G, Lopez, L, Lopez-Botet, M, Lovett-Racke, AE, Lubberts, E, Luche, H, Ludewig, B, Lugli, E, Lunemann, S, Maecker, HT, Maggi, L, Maguire, O, Mair, F, Mair, KH, Mantovani, A, Manz, RA, Marshall, AJ, Martinez-Romero, A, Martrus, G, Marventano, I, Maslinski, W, Matarese, G, Mattioli, AV, Maueroder, C, Mazzoni, A, McCluskey, J, McGrath, M, McGuire, HM, McInnes, IB, Mei, HE, Melchers, F, Melzer, S, Mielenz, D, Miller, SD, Mills, KHG, Minderman, H, Mjosberg, J, Moore, J, Moran, B, Moretta, L, Mosmann, TR, Mueller, S, Multhoff, G, Munoz, LE, Munz, C, Nakayama, T, Nasi, M, Neumann, K, Ng, LG, Niedobitek, A, Nourshargh, S, Nunez, G, O'Connor, J-E, Ochel, A, Oja, A, Ordonez, D, Orfao, A, Orlowski-Oliver, E, Ouyang, W, Oxenius, A, Palankar, R, Panse, I, Pattanapanyasat, K, Paulsen, M, Pavlinic, D, Penter, L, Peterson, P, Peth, C, Petriz, J, Piancone, F, Pickl, WF, Piconese, S, Pinti, M, Pockley, AG, Podolska, MJ, Poon, Z, Pracht, K, Prinz, I, Pucillo, CEM, Quataert, SA, Quatrini, L, Quinn, KM, Radbruch, H, Radstake, TRDJ, Rahmig, S, Rahn, H-P, Rajwa, B, Ravichandran, G, Raz, Y, Rebhahn, JA, Recktenwald, D, Reimer, D, Reis e Sousa, C, Remmerswaal, EBM, Richter, L, Rico, LG, Riddell, A, Rieger, AM, Robinson, JP, Romagnani, C, Rubartelli, A, Ruland, J, Saalmueller, A, Saeys, Y, Saito, T, Sakaguchi, S, Sala-de-Oyanguren, F, Samstag, Y, Sanderson, S, Sandrock, I, Santoni, A, Sanz, RB, Saresella, M, Sautes-Fridman, C, Sawitzki, B, Schadt, L, Scheffold, A, Scherer, HU, Schiemann, M, Schildberg, FA, Schimisky, E, Schlitzer, A, Schlosser, J, Schmid, S, Schmitt, S, Schober, K, Schraivogel, D, Schuh, W, Schueler, T, Schulte, R, Schulz, AR, Schulz, SR, Scotta, C, Scott-Algara, D, Sester, DP, Shankey, TV, Silva-Santos, B, Simon, AK, Sitnik, KM, Sozzani, S, Speiser, DE, Spidlen, J, Stahlberg, A, Stall, AM, Stanley, N, Stark, R, Stehle, C, Steinmetz, T, Stockinger, H, Takahama, Y, Takeda, K, Tan, L, Tarnok, A, Tiegs, G, Toldi, G, Tornack, J, Traggiai, E, Trebak, M, Tree, TIM, Trotter, J, Trowsdale, J, Tsoumakidou, M, Ulrich, H, Urbanczyk, S, van de Veen, W, van den Broek, M, van der Pol, E, Van Gassen, S, Van Isterdael, G, van Lier, RAW, Veldhoen, M, Vento-Asturias, S, Vieira, P, Voehringer, D, Volk, H-D, von Borstel, A, von Volkmann, K, Waisman, A, Walker, RV, Wallace, PK, Wang, SA, Wang, XM, Ward, MD, Ward-Hartstonge, KA, Warnatz, K, Warnes, G, Warth, S, Waskow, C, Watson, JV, Watzl, C, Wegener, L, Weisenburger, T, Wiedemann, A, Wienands, J, Wilharm, A, Wilkinson, RJ, Willimsky, G, Wing, JB, Winkelmann, R, Winkler, TH, Wirz, OF, Wong, A, Wurst, P, Yang, JHM, Yang, J, Yazdanbakhsh, M, Yu, L, Yue, A, Zhang, H, Zhao, Y, Ziegler, SM, Zielinski, C, Zimmermann, J, Zychlinsky, A, Cossarizza, A, Chang, H-D, Radbruch, A, Acs, A, Adam, D, Adam-Klages, S, Agace, WW, Aghaeepour, N, Akdis, M, Allez, M, Almeida, LN, Alvisi, G, Anderson, G, Andrae, I, Annunziato, F, Anselmo, A, Bacher, P, Baldari, CT, Bari, S, Barnaba, V, Barros-Martins, J, Battistini, L, Bauer, W, Baumgart, S, Baumgarth, N, Baumjohann, D, Baying, B, Bebawy, M, Becher, B, Beisker, W, Benes, V, Beyaert, R, Blanco, A, Boardman, DA, Bogdan, C, Borger, JG, Borsellino, G, Boulais, PE, Bradford, JA, Brenner, D, Brinkman, RR, Brooks, AES, Busch, DH, Buescher, M, Bushnell, TP, Calzetti, F, Cameron, G, Cammarata, I, Cao, X, Cardell, SL, Casola, S, Cassatella, MA, Cavani, A, Celada, A, Chatenoud, L, Chattopadhyay, PK, Chow, S, Christakou, E, Cicin-Sain, L, Clerici, M, Colombo, FS, Cook, L, Cooke, A, Cooper, AM, Corbett, AJ, Cosma, A, Cosmi, L, Coulie, PG, Cumano, A, Cvetkovic, L, Dang, VD, Dang-Heine, C, Davey, MS, Davies, D, De Biasi, S, Del Zotto, G, Dela Cruz, GV, Delacher, M, Della Bella, S, Dellabona, P, Deniz, G, Dessing, M, Di Santo, JP, Diefenbach, A, Dieli, F, Dolf, A, Doerner, T, Dress, RJ, Dudziak, D, Dustin, M, Dutertre, C-A, Ebner, F, Eckle, SBG, Edinger, M, Eede, P, Ehrhardt, GRA, Eich, M, Engel, P, Engelhardt, B, Erdei, A, Esser, C, Everts, B, Evrard, M, Falk, CS, Fehniger, TA, Felipo-Benavent, M, Ferry, H, Feuerer, M, Filby, A, Filkor, K, Fillatreau, S, Follo, M, Foerster, I, Foster, J, Foulds, GA, Frehse, B, Frenette, PS, Frischbutter, S, Fritzsche, W, Galbraith, DW, Gangaev, A, Garbi, N, Gaudilliere, B, Gazzinelli, RT, Geginat, J, Gerner, W, Gherardin, NA, Ghoreschi, K, Gibellini, L, Ginhoux, F, Goda, K, Godfrey, DI, Goettlinger, C, Gonzalez-Navajas, JM, Goodyear, CS, Gori, A, Grogan, JL, Grummitt, D, Gruetzkau, A, Haftmann, C, Hahn, J, Hammad, H, Haemmerling, G, Hansmann, L, Hansson, G, Harpur, CM, Hartmann, S, Hauser, A, Hauser, AE, Haviland, DL, Hedley, D, Hernandez, DC, Herrera, G, Herrmann, M, Hess, C, Hoefer, T, Hoffmann, P, Hogquist, K, Holland, T, Hollt, T, Holmdahl, R, Hombrink, P, Houston, JP, Hoyer, BF, Huang, B, Huang, F-P, Huber, JE, Huehn, J, Hundemer, M, Hunter, CA, Hwang, WYK, Iannone, A, Ingelfinger, F, Ivison, SM, Jaeck, H-M, Jani, PK, Javega, B, Jonjic, S, Kaiser, T, Kalina, T, Kamradt, T, Kaufmann, SHE, Keller, B, Ketelaars, SLC, Khalilnezhad, A, Khan, S, Kisielow, J, Klenerman, P, Knopf, J, Koay, H-F, Kobow, K, Kolls, JK, Kong, WT, Kopf, M, Korn, T, Kriegsmann, K, Kristyanto, H, Kroneis, T, Krueger, A, Kuehne, J, Kukat, C, Kunkel, D, Kunze-Schumacher, H, Kurosaki, T, Kurts, C, Kvistborg, P, Kwok, I, Landry, J, Lantz, O, Lanuti, P, LaRosa, F, Lehuen, A, LeibundGut-Landmann, S, Leipold, MD, Leung, LYT, Levings, MK, Lino, AC, Liotta, F, Litwin, V, Liu, Y, Ljunggren, H-G, Lohoff, M, Lombardi, G, Lopez, L, Lopez-Botet, M, Lovett-Racke, AE, Lubberts, E, Luche, H, Ludewig, B, Lugli, E, Lunemann, S, Maecker, HT, Maggi, L, Maguire, O, Mair, F, Mair, KH, Mantovani, A, Manz, RA, Marshall, AJ, Martinez-Romero, A, Martrus, G, Marventano, I, Maslinski, W, Matarese, G, Mattioli, AV, Maueroder, C, Mazzoni, A, McCluskey, J, McGrath, M, McGuire, HM, McInnes, IB, Mei, HE, Melchers, F, Melzer, S, Mielenz, D, Miller, SD, Mills, KHG, Minderman, H, Mjosberg, J, Moore, J, Moran, B, Moretta, L, Mosmann, TR, Mueller, S, Multhoff, G, Munoz, LE, Munz, C, Nakayama, T, Nasi, M, Neumann, K, Ng, LG, Niedobitek, A, Nourshargh, S, Nunez, G, O'Connor, J-E, Ochel, A, Oja, A, Ordonez, D, Orfao, A, Orlowski-Oliver, E, Ouyang, W, Oxenius, A, Palankar, R, Panse, I, Pattanapanyasat, K, Paulsen, M, Pavlinic, D, Penter, L, Peterson, P, Peth, C, Petriz, J, Piancone, F, Pickl, WF, Piconese, S, Pinti, M, Pockley, AG, Podolska, MJ, Poon, Z, Pracht, K, Prinz, I, Pucillo, CEM, Quataert, SA, Quatrini, L, Quinn, KM, Radbruch, H, Radstake, TRDJ, Rahmig, S, Rahn, H-P, Rajwa, B, Ravichandran, G, Raz, Y, Rebhahn, JA, Recktenwald, D, Reimer, D, Reis e Sousa, C, Remmerswaal, EBM, Richter, L, Rico, LG, Riddell, A, Rieger, AM, Robinson, JP, Romagnani, C, Rubartelli, A, Ruland, J, Saalmueller, A, Saeys, Y, Saito, T, Sakaguchi, S, Sala-de-Oyanguren, F, Samstag, Y, Sanderson, S, Sandrock, I, Santoni, A, Sanz, RB, Saresella, M, Sautes-Fridman, C, Sawitzki, B, Schadt, L, Scheffold, A, Scherer, HU, Schiemann, M, Schildberg, FA, Schimisky, E, Schlitzer, A, Schlosser, J, Schmid, S, Schmitt, S, Schober, K, Schraivogel, D, Schuh, W, Schueler, T, Schulte, R, Schulz, AR, Schulz, SR, Scotta, C, Scott-Algara, D, Sester, DP, Shankey, TV, Silva-Santos, B, Simon, AK, Sitnik, KM, Sozzani, S, Speiser, DE, Spidlen, J, Stahlberg, A, Stall, AM, Stanley, N, Stark, R, Stehle, C, Steinmetz, T, Stockinger, H, Takahama, Y, Takeda, K, Tan, L, Tarnok, A, Tiegs, G, Toldi, G, Tornack, J, Traggiai, E, Trebak, M, Tree, TIM, Trotter, J, Trowsdale, J, Tsoumakidou, M, Ulrich, H, Urbanczyk, S, van de Veen, W, van den Broek, M, van der Pol, E, Van Gassen, S, Van Isterdael, G, van Lier, RAW, Veldhoen, M, Vento-Asturias, S, Vieira, P, Voehringer, D, Volk, H-D, von Borstel, A, von Volkmann, K, Waisman, A, Walker, RV, Wallace, PK, Wang, SA, Wang, XM, Ward, MD, Ward-Hartstonge, KA, Warnatz, K, Warnes, G, Warth, S, Waskow, C, Watson, JV, Watzl, C, Wegener, L, Weisenburger, T, Wiedemann, A, Wienands, J, Wilharm, A, Wilkinson, RJ, Willimsky, G, Wing, JB, Winkelmann, R, Winkler, TH, Wirz, OF, Wong, A, Wurst, P, Yang, JHM, Yang, J, Yazdanbakhsh, M, Yu, L, Yue, A, Zhang, H, Zhao, Y, Ziegler, SM, Zielinski, C, Zimmermann, J, and Zychlinsky, A

Abstract

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.

Published
2019

19. IL-10-producing forkhead box protein 3-negative regulatory T cells inhibit B-cell responses and are involved in systemic lupus erythematosus

Author

Facciotti, F, Gagliani, N, Häringer, B, Alfen, J, Penatti, A, Maglie, S, Paroni, M, Iseppon, A, Moro, M, Crosti, M, Stölzel, K, Romagnani, C, Moroni, G, Ingegnoli, F, Torretta, S, Pignataro, L, Annoni, A, Russo, F, Pagani, M, Abrignani, S, Meroni, P, Flavell, R, Geginat, J, Facciotti F, Gagliani N, Häringer B, Alfen JS, Penatti A, Maglie S, Paroni M, Iseppon A, Moro M, Crosti MC, Stölzel K, Romagnani C, Moroni G, Ingegnoli F, Torretta S, Pignataro L, Annoni A, Russo F, Pagani M, Abrignani S, Meroni P, Flavell R, Geginat J, Facciotti, F, Gagliani, N, Häringer, B, Alfen, J, Penatti, A, Maglie, S, Paroni, M, Iseppon, A, Moro, M, Crosti, M, Stölzel, K, Romagnani, C, Moroni, G, Ingegnoli, F, Torretta, S, Pignataro, L, Annoni, A, Russo, F, Pagani, M, Abrignani, S, Meroni, P, Flavell, R, Geginat, J, Facciotti F, Gagliani N, Häringer B, Alfen JS, Penatti A, Maglie S, Paroni M, Iseppon A, Moro M, Crosti MC, Stölzel K, Romagnani C, Moroni G, Ingegnoli F, Torretta S, Pignataro L, Annoni A, Russo F, Pagani M, Abrignani S, Meroni P, Flavell R, and Geginat J

Published
2016

22. Absence of a role for interleukin-13 in inflammatory bowel disease

Author

Biancheri, P, Di Sabatino, A, Ammoscato, F, Facciotti, F, Caprioli, F, Curciarello, R, Hoque, S, Ghanbari, A, Joe-Njoku, I, Giuffrida, P, Rovedatti, L, Geginat, J, Corazza, G, Macdonald, T, Biancheri P, Di Sabatino A, Ammoscato F, Facciotti F, Caprioli F, Curciarello R, Hoque SS, Ghanbari A, Joe-Njoku I, Giuffrida P, Rovedatti L, Geginat J, Corazza GR, MacDonald TT, Biancheri, P, Di Sabatino, A, Ammoscato, F, Facciotti, F, Caprioli, F, Curciarello, R, Hoque, S, Ghanbari, A, Joe-Njoku, I, Giuffrida, P, Rovedatti, L, Geginat, J, Corazza, G, Macdonald, T, Biancheri P, Di Sabatino A, Ammoscato F, Facciotti F, Caprioli F, Curciarello R, Hoque SS, Ghanbari A, Joe-Njoku I, Giuffrida P, Rovedatti L, Geginat J, Corazza GR, and MacDonald TT

Abstract

IL-13 has been implicated in the pathogenesis of ulcerative colitis (UC), and may have a role in animal models of gut fibrosis. We studied the involvement of IL-13 in inflammation and fibrosis in UC and Crohn's disease (CD). Intestinal biopsies and anti-CD3/CD28- or anti-CD2/CD28-stimulated lamina propria mononuclear cells from UC and CD patients and control subjects were cultured, and IL-13, IL-4, IL-5, IL-17A and IFN- production was measured. Mucosal IL-13-producing cells were characterised by flow cytometry. Gut explants from strictured CD, non-strictured CD and healthy donors were cultured ex vivo, and secreted IL-13, IL-1 and collagen were measured. IL-13 production by mucosal explants and activated lamina propria mononuclear cells did not differ between CD, UC and control subjects, and was at least a log lower than IFN- and IL-17A. IL-13-producing cells, and in particular natural killer T cells, were uniformly low in all groups. IL-4 and IL-5 were undetectable in culture supernatants. Explants of CD strictures produced low amounts of IL-13, whereas IL-1 and collagen were elevated. We could not confirm that UC or strictured CD are associated with elevated IL-13 production. These data suggest that an anti-IL-13 Ab would not be an appropriate therapeutic strategy in inflammatory bowel disease.

Published
2014

23. Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells

Author

De Simone, M., Arrigoni, A., Rossetti, G., Gruarin, P., Ranzani, V., Politano, C., Bonnal, R.J., Provasi, E., Sarnicola, M.L., Panzeri, I., Moro, M., Crosti, M., Mazzara, S., Vaira, V., Bosari, S., Palleschi, A., Santambrogio, L., Bovo, G., Zucchini, N., Totis, M., Gianotti, L., Cesana, G., Perego, R.A., Maroni, N., Pisani Ceretti, A., Opocher, E., De Francesco, R., Geginat, J., Stunnenberg, H., Abrignani, S., Pagani, M., De Simone, M., Arrigoni, A., Rossetti, G., Gruarin, P., Ranzani, V., Politano, C., Bonnal, R.J., Provasi, E., Sarnicola, M.L., Panzeri, I., Moro, M., Crosti, M., Mazzara, S., Vaira, V., Bosari, S., Palleschi, A., Santambrogio, L., Bovo, G., Zucchini, N., Totis, M., Gianotti, L., Cesana, G., Perego, R.A., Maroni, N., Pisani Ceretti, A., Opocher, E., De Francesco, R., Geginat, J., Stunnenberg, H., Abrignani, S., and Pagani, M.

Abstract

Contains fulltext : 161837.pdf (publisher's version ) (Open Access), Tumor-infiltrating regulatory T lymphocytes (Treg) can suppress effector T cells specific for tumor antigens. Deeper molecular definitions of tumor-infiltrating-lymphocytes could thus offer therapeutic opportunities. Transcriptomes of T helper 1 (Th1), Th17, and Treg cells infiltrating colorectal or non-small-cell lung cancers were compared to transcriptomes of the same subsets from normal tissues and validated at the single-cell level. We found that tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints, and expressed on the cell surfaces specific signature molecules such as interleukin-1 receptor 2 (IL1R2), programmed death (PD)-1 Ligand1, PD-1 Ligand2, and CCR8 chemokine, which were not previously described on Treg cells. Remarkably, high expression in whole-tumor samples of Treg cell signature genes, such as LAYN, MAGEH1, or CCR8, correlated with poor prognosis. Our findings provide insights into the molecular identity and functions of human tumor-infiltrating Treg cells and define potential targets for tumor immunotherapy.

Published
2016

24. Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells

Author

De Simone, M, Arrigoni, A, Rossetti, G, Gruarin, P, Ranzani, V, Politano, C, Bonnal, R, Provasi, E, Sarnicola, M, Panzeri, I, Moro, M, Crosti, M, Mazzara, S, Vaira, V, Bosari, S, Palleschi, A, Santambrogio, L, Bovo, G, Zucchini, N, Totis, M, Gianotti, L, Cesana, G, Perego, R, Maroni, N, Pisani Ceretti, A, Opocher, E, De Francesco, R, Geginat, J, Stunnenberg, H, Abrignani, S, Pagani, M, Bonnal, RJP, Sarnicola, ML, Perego, RA, Stunnenberg, HG, De Simone, M, Arrigoni, A, Rossetti, G, Gruarin, P, Ranzani, V, Politano, C, Bonnal, R, Provasi, E, Sarnicola, M, Panzeri, I, Moro, M, Crosti, M, Mazzara, S, Vaira, V, Bosari, S, Palleschi, A, Santambrogio, L, Bovo, G, Zucchini, N, Totis, M, Gianotti, L, Cesana, G, Perego, R, Maroni, N, Pisani Ceretti, A, Opocher, E, De Francesco, R, Geginat, J, Stunnenberg, H, Abrignani, S, Pagani, M, Bonnal, RJP, Sarnicola, ML, Perego, RA, and Stunnenberg, HG

Abstract

Tumor-infiltrating regulatory T lymphocytes (Treg) can suppress effector T cells specific for tumor antigens. Deeper molecular definitions of tumor-infiltrating-lymphocytes could thus offer therapeutic opportunities. Transcriptomes of T helper 1 (Th1), Th17, and Treg cells infiltrating colorectal or non-small-cell lung cancers were compared to transcriptomes of the same subsets from normal tissues and validated at the single-cell level. We found that tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints, and expressed on the cell surfaces specific signature molecules such as interleukin-1 receptor 2 (IL1R2), programmed death (PD)-1 Ligand1, PD-1 Ligand2, and CCR8 chemokine, which were not previously described on Treg cells. Remarkably, high expression in whole-tumor samples of Treg cell signature genes, such as LAYN, MAGEH1, or CCR8, correlated with poor prognosis. Our findings provide insights into the molecular identity and functions of human tumor-infiltrating Treg cells and define potential targets for tumor immunotherapy.

Published
2016

33. Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate AP-1 activity

Author

Bianchi, E, Denti, S, Granata, A, Bossi, G, Geginat, J, Villa, A, Rogge, L, Pardi, R, Pardi, R., VILLA, ANTONELLO, Bianchi, E, Denti, S, Granata, A, Bossi, G, Geginat, J, Villa, A, Rogge, L, Pardi, R, Pardi, R., and VILLA, ANTONELLO

Abstract

Integrin adhesion receptors transduce signals that control complex cell functions which require the regulation of gene expression, such as proliferation, differentiation and survival. Their intracellular domain has no catalytic function, indicating that interaction with other transducing molecules is crucial for integrin-mediated signalling. Here we have identified a protein that interacts with the cytoplasmic domain of the beta2 subunit of the alphaL/beta2 integrin LFA-1. This protein is JAB1 (Jun activation domain-binding protein 1), a coactivator of the c-Jun transcription factor. We found that JAB1 is present both in the nucleus and in the cytoplasm of cells and that a fraction of JAB1 colocalizes with LFA-1 at the cell membrane. LFA-1 engagement is followed by an increase of the nuclear pool of JAB1, paralleled by enhanced binding of c-Jun-containing AP-1 complexes to their DNA consensus site and increased transactivation of an AP-1-dependent promoter. We suggest that signalling through the LFA-1 integrin may affect c-Jun-driven transcription by regulating JAB1 nuclear localization. This represents a new pathway for integrin-dependent modulation of gene expression.

Published
2000

36. Cytokine-driven proliferation and differentiation of human nai¨ve, central memory and effector memory CD4+ T cells

Author

Geginat, J., Sallusto, F., and Lanzavecchia, A.

Subjects
*T cells, *HOMEOSTASIS
Abstract

Memory T lymphocytes divide in vivo in the absence of antigen maintaining a pool of central memory (TCM) and effector memory cells (TEM) with distinct effector function and homing capacity. We compared human CD4+ nai¨ve T, TCM and TEM cells for their capacity to proliferate in response to cytokines, which have been implicated in T cell homeostasis. Interleukin (IL)-7 and IL-15 expanded with very high efficiency TEM, while TCM were less responsive and nai¨ve T cells did not respond at all. Dendritic cell (DC)-derived cytokines allowed nai¨ve T cells to respond selectively to IL-4 and potently boosted the response of TCM to IL-7 and IL-15 by increasing the expression of the IL-2/IL-15Rß and the common γ chain (γc). The ERK and the p38 MAP kinases were selectively required for TCR and cytokine-driven proliferation, respectively. Importantly, in cytokine-driven cultures TCM proliferated and some of the proliferating cells acquired effector function and non-lymphoid tissue homing capacity. Ex vivo BrdU incorporation experiments showed that both TCM and TEM proliferated under steady state conditions in vivo. Altogether these results provide a plausible mechanism for the maintenance of a polyclonal and functionally diverse repertoire of human CD4+ memory T cells and for a sustained antigen-independent generation of TEM from a pool of TCM cells. [Copyright &y& Elsevier]

Published
2003
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39. Eomesodermin controls a unique differentiation program in human IL‐10 and IFN‐γ coproducing regulatory T cells

Author

Grazisa Rossetti, Martina Martinovic, Paola Larghi, Valeria Ranzani, Maria Lucia Sarnicola, Maria Ester Bernardo, Barbara Häringer, Riccardo L. Rossi, Federica Facciotti, Sergio Abrignani, Paola Gruarin, Mariacristina Crosti, Marco De Simone, Flavio Caprioli, Chiara Vasco, Stefano Maglie, Roberto Bosotti, Franco Locatelli, Jens Geginat, Massimiliano Pagani, Johanna S. Noddings, Monica Moro, Gruarin, P, Maglie, S, De Simone, M, Haringer, B, Vasco, C, Ranzani, V, Bosotti, R, Noddings, J, Larghi, P, Facciotti, F, Sarnicola, M, Martinovic, M, Crosti, M, Moro, M, Rossi, R, Bernardo, M, Caprioli, F, Locatelli, F, Rossetti, G, Abrignani, S, Pagani, M, Geginat, J, Gruarin, P., Maglie, S., De Simone, M., Haringer, B., Vasco, C., Ranzani, V., Bosotti, R., Noddings, J. S., Larghi, P., Facciotti, F., Sarnicola, M. L., Martinovic, M., Crosti, M., Moro, M., Rossi, R. L., Bernardo, M. E., Caprioli, F., Locatelli, F., Rossetti, G., Abrignani, S., Pagani, M., and Geginat, J.

Subjects
0301 basic medicine, Immunology, Regulatory T&nbsp, Graft vs Host Disease, Eomesodermin, T-Lymphocytes, Regulatory, Granzymes, Interferon-gamma, Mice, 03 medical and health sciences, 0302 clinical medicine, T-Lymphocyte Subsets, Animals, Humans, Immunology and Allergy, Cytotoxic T cell, Cell Lineage, Granzyme K, Cells, Cultured, Regulatory T cells, CD40, biology, Effector, T-cell receptor, Cell Differentiation, Th1 Cells, Inflammatory Bowel Diseases, differentiation, EOMES, granzyme K, regulatory T cells, Th17, Differentiation, EOMES, Granzyme K, Regulatory T cells, Th17, Interleukin-10, Cell biology, Interleukin 10, 030104 developmental biology, Gene Expression Regulation, Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA, Granzyme, Differentiation, biology.protein, cells, T-Box Domain Proteins, Immunologic Memory, 030215 immunology
Abstract

Whether human IL-10-producing regulatory Tcells (“Tr1”) represent a distinct differentiation lineage or an unstable activation stage remains a key unsolved issue. Here, we report that Eomesodermin (Eomes) acted as a lineage-defining transcription factor in human IFN-γ/IL-10 coproducing Tr1-like cells. In vivo occurring Tr1-like cells expressed Eomes, and were clearly distinct from all other CD4 + T-cell subsets, including conventional cytotoxic CD4 + Tcells. They expressed Granzyme (Gzm) K, but had lost CD40L and IL-7R expression. Eomes antagonized the Th17 fate, and directly controlled IFN-γ and GzmK expression. However, Eomes binding to the IL-10 promoter was not detectable in human CD4 + Tcells, presumably because critical Tbox binding sites of the mouse were not conserved. A precommitment to a Tr1-like fate, i.e. concominant induction of Eomes, GzmK, and IFN-γ, was promoted by IL-4 and IL-12-secreting myeloid dendritic cells. Consistently, Th1 effector memory cells contained precommitted Eomes + GzmK + Tcells. Stimulation with T-cell receptor (TCR) agonists and IL-27 promoted the generation of Tr1-like effector cells by inducing switching from CD40L to IL-10. Importantly, CD4 + Eomes + T-cell subsets were present in lymphoid and nonlymphoid tissues, and their frequencies varied systemically in patients with inflammatory bowel disease and graft-versus-host disease. We propose that Eomes + Tr1-like cells are effector cells of a unique GzmK-expressing CD4 + T-cell subset.

Published
2018

40. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)

Author

Andrea Cossarizza, Hyun‐Dong Chang, Andreas Radbruch, Sergio Abrignani, Richard Addo, Mübeccel Akdis, Immanuel Andrä, Francesco Andreata, Francesco Annunziato, Eduardo Arranz, Petra Bacher, Sudipto Bari, Vincenzo Barnaba, Joana Barros‐Martins, Dirk Baumjohann, Cristian G. Beccaria, David Bernardo, Dominic A. Boardman, Jessica Borger, Chotima Böttcher, Leonie Brockmann, Marie Burns, Dirk H. Busch, Garth Cameron, Ilenia Cammarata, Antonino Cassotta, Yinshui Chang, Fernando Gabriel Chirdo, Eleni Christakou, Luka Čičin‐Šain, Laura Cook, Alexandra J. Corbett, Rebecca Cornelis, Lorenzo Cosmi, Martin S. Davey, Sara De Biasi, Gabriele De Simone, Genny del Zotto, Michael Delacher, Francesca Di Rosa, James Di Santo, Andreas Diefenbach, Jun Dong, Thomas Dörner, Regine J. Dress, Charles‐Antoine Dutertre, Sidonia B. G. Eckle, Pascale Eede, Maximilien Evrard, Christine S. Falk, Markus Feuerer, Simon Fillatreau, Aida Fiz‐Lopez, Marie Follo, Gemma A. Foulds, Julia Fröbel, Nicola Gagliani, Giovanni Galletti, Anastasia Gangaev, Natalio Garbi, José Antonio Garrote, Jens Geginat, Nicholas A. Gherardin, Lara Gibellini, Florent Ginhoux, Dale I. Godfrey, Paola Gruarin, Claudia Haftmann, Leo Hansmann, Christopher M. Harpur, Adrian C. Hayday, Guido Heine, Daniela Carolina Hernández, Martin Herrmann, Oliver Hoelsken, Qing Huang, Samuel Huber, Johanna E. Huber, Jochen Huehn, Michael Hundemer, William Y. K. Hwang, Matteo Iannacone, Sabine M. Ivison, Hans‐Martin Jäck, Peter K. Jani, Baerbel Keller, Nina Kessler, Steven Ketelaars, Laura Knop, Jasmin Knopf, Hui‐Fern Koay, Katja Kobow, Katharina Kriegsmann, H. Kristyanto, Andreas Krueger, Jenny F. Kuehne, Heike Kunze‐Schumacher, Pia Kvistborg, Immanuel Kwok, Daniela Latorre, Daniel Lenz, Megan K. Levings, Andreia C. Lino, Francesco Liotta, Heather M. Long, Enrico Lugli, Katherine N. MacDonald, Laura Maggi, Mala K. Maini, Florian Mair, Calin Manta, Rudolf Armin Manz, Mir‐Farzin Mashreghi, Alessio Mazzoni, James McCluskey, Henrik E. Mei, Fritz Melchers, Susanne Melzer, Dirk Mielenz, Leticia Monin, Lorenzo Moretta, Gabriele Multhoff, Luis Enrique Muñoz, Miguel Muñoz‐Ruiz, Franziska Muscate, Ambra Natalini, Katrin Neumann, Lai Guan Ng, Antonia Niedobitek, Jana Niemz, Larissa Nogueira Almeida, Samuele Notarbartolo, Lennard Ostendorf, Laura J. Pallett, Amit A. Patel, Gulce Itir Percin, Giovanna Peruzzi, Marcello Pinti, A. Graham Pockley, Katharina Pracht, Immo Prinz, Irma Pujol‐Autonell, Nadia Pulvirenti, Linda Quatrini, Kylie M. Quinn, Helena Radbruch, Hefin Rhys, Maria B. Rodrigo, Chiara Romagnani, Carina Saggau, Shimon Sakaguchi, Federica Sallusto, Lieke Sanderink, Inga Sandrock, Christine Schauer, Alexander Scheffold, Hans U. Scherer, Matthias Schiemann, Frank A. Schildberg, Kilian Schober, Janina Schoen, Wolfgang Schuh, Thomas Schüler, Axel R. Schulz, Sebastian Schulz, Julia Schulze, Sonia Simonetti, Jeeshan Singh, Katarzyna M. Sitnik, Regina Stark, Sarah Starossom, Christina Stehle, Franziska Szelinski, Leonard Tan, Attila Tarnok, Julia Tornack, Timothy I. M. Tree, Jasper J. P. van Beek, Willem van de Veen, Klaas van Gisbergen, Chiara Vasco, Nikita A. Verheyden, Anouk von Borstel, Kirsten A. Ward‐Hartstonge, Klaus Warnatz, Claudia Waskow, Annika Wiedemann, Anneke Wilharm, James Wing, Oliver Wirz, Jens Wittner, Jennie H. M. Yang, Juhao Yang, Rolf M. Schwiete Foundation, Associazione Italiana per la Ricerca sul Cancro, German Research Foundation, National Institutes of Health (US), European Commission, AII - Inflammatory diseases, Cossarizza, A, Chang, H, Radbruch, A, Abrignani, S, Addo, R, Akdis, M, Andra, I, Andreata, F, Annunziato, F, Arranz, E, Bacher, P, Bari, S, Barnaba, V, Barros-Martins, J, Baumjohann, D, Beccaria, C, Bernardo, D, Boardman, D, Borger, J, Bottcher, C, Brockmann, L, Burns, M, Busch, D, Cameron, G, Cammarata, I, Cassotta, A, Chang, Y, Chirdo, F, Christakou, E, Cicin-Sain, L, Cook, L, Corbett, A, Cornelis, R, Cosmi, L, Davey, M, De Biasi, S, De Simone, G, del Zotto, G, Delacher, M, Di Rosa, F, Santo, J, Diefenbach, A, Dong, J, Dorner, T, Dress, R, Dutertre, C, Eckle, S, Eede, P, Evrard, M, Falk, C, Feuerer, M, Fillatreau, S, Fiz-Lopez, A, Follo, M, Foulds, G, Frobel, J, Gagliani, N, Galletti, G, Gangaev, A, Garbi, N, Garrote, J, Geginat, J, Gherardin, N, Gibellini, L, Ginhoux, F, Godfrey, D, Gruarin, P, Haftmann, C, Hansmann, L, Harpur, C, Hayday, A, Heine, G, Hernandez, D, Herrmann, M, Hoelsken, O, Huang, Q, Huber, S, Huber, J, Huehn, J, Hundemer, M, Hwang, W, Iannacone, M, Ivison, S, Jack, H, Jani, P, Keller, B, Kessler, N, Ketelaars, S, Knop, L, Knopf, J, Koay, H, Kobow, K, Kriegsmann, K, Kristyanto, H, Krueger, A, Kuehne, J, Kunze-Schumacher, H, Kvistborg, P, Kwok, I, Latorre, D, Lenz, D, Levings, M, Lino, A, Liotta, F, Long, H, Lugli, E, Macdonald, K, Maggi, L, Maini, M, Mair, F, Manta, C, Manz, R, Mashreghi, M, Mazzoni, A, Mccluskey, J, Mei, H, Melchers, F, Melzer, S, Mielenz, D, Monin, L, Moretta, L, Multhoff, G, Munoz, L, Munoz-Ruiz, M, Muscate, F, Natalini, A, Neumann, K, Ng, L, Niedobitek, A, Niemz, J, Almeida, L, Notarbartolo, S, Ostendorf, L, Pallett, L, Patel, A, Percin, G, Peruzzi, G, Pinti, M, Pockley, A, Pracht, K, Prinz, I, Pujol-Autonell, I, Pulvirenti, N, Quatrini, L, Quinn, K, Radbruch, H, Rhys, H, Rodrigo, M, Romagnani, C, Saggau, C, Sakaguchi, S, Sallusto, F, Sanderink, L, Sandrock, I, Schauer, C, Scheffold, A, Scherer, H, Schiemann, M, Schildberg, F, Schober, K, Schoen, J, Schuh, W, Schuler, T, Schulz, A, Schulz, S, Schulze, J, Simonetti, S, Singh, J, Sitnik, K, Stark, R, Starossom, S, Stehle, C, Szelinski, F, Tan, L, Tarnok, A, Tornack, J, Tree, T, van Beek, J, van de Veen, W, van Gisbergen, K, Vasco, C, Verheyden, N, von Borstel, A, Ward-Hartstonge, K, Warnatz, K, Waskow, C, Wiedemann, A, Wilharm, A, Wing, J, Wirz, O, Wittner, J, Yang, J, Publica, Cossarizza, A., Chang, H. -D., Radbruch, A., Abrignani, S., Addo, R., Akdis, M., Andra, I., Andreata, F., Annunziato, F., Arranz, E., Bacher, P., Bari, S., Barnaba, V., Barros-Martins, J., Baumjohann, D., Beccaria, C. G., Bernardo, D., Boardman, D. A., Borger, J., Bottcher, C., Brockmann, L., Burns, M., Busch, D. H., Cameron, G., Cammarata, I., Cassotta, A., Chang, Y., Chirdo, F. G., Christakou, E., Cicin-Sain, L., Cook, L., Corbett, A. J., Cornelis, R., Cosmi, L., Davey, M. S., De Biasi, S., De Simone, G., del Zotto, G., Delacher, M., Di Rosa, F., Santo, J. D., Diefenbach, A., Dong, J., Dorner, T., Dress, R. J., Dutertre, C. -A., Eckle, S. B. G., Eede, P., Evrard, M., Falk, C. S., Feuerer, M., Fillatreau, S., Fiz-Lopez, A., Follo, M., Foulds, G. A., Frobel, J., Gagliani, N., Galletti, G., Gangaev, A., Garbi, N., Garrote, J. A., Geginat, J., Gherardin, N. A., Gibellini, L., Ginhoux, F., Godfrey, D. I., Gruarin, P., Haftmann, C., Hansmann, L., Harpur, C. M., Hayday, A. C., Heine, G., Hernandez, D. C., Herrmann, M., Hoelsken, O., Huang, Q., Huber, S., Huber, J. E., Huehn, J., Hundemer, M., Hwang, W. Y. K., Iannacone, M., Ivison, S. M., Jack, H. -M., Jani, P. K., Keller, B., Kessler, N., Ketelaars, S., Knop, L., Knopf, J., Koay, H. -F., Kobow, K., Kriegsmann, K., Kristyanto, H., Krueger, A., Kuehne, J. F., Kunze-Schumacher, H., Kvistborg, P., Kwok, I., Latorre, D., Lenz, D., Levings, M. K., Lino, A. C., Liotta, F., Long, H. M., Lugli, E., Macdonald, K. N., Maggi, L., Maini, M. K., Mair, F., Manta, C., Manz, R. A., Mashreghi, M. -F., Mazzoni, A., Mccluskey, J., Mei, H. E., Melchers, F., Melzer, S., Mielenz, D., Monin, L., Moretta, L., Multhoff, G., Munoz, L. E., Munoz-Ruiz, M., Muscate, F., Natalini, A., Neumann, K., Ng, L. G., Niedobitek, A., Niemz, J., Almeida, L. N., Notarbartolo, S., Ostendorf, L., Pallett, L. J., Patel, A. A., Percin, G. I., Peruzzi, G., Pinti, M., Pockley, A. G., Pracht, K., Prinz, I., Pujol-Autonell, I., Pulvirenti, N., Quatrini, L., Quinn, K. M., Radbruch, H., Rhys, H., Rodrigo, M. B., Romagnani, C., Saggau, C., Sakaguchi, S., Sallusto, F., Sanderink, L., Sandrock, I., Schauer, C., Scheffold, A., Scherer, H. U., Schiemann, M., Schildberg, F. A., Schober, K., Schoen, J., Schuh, W., Schuler, T., Schulz, A. R., Schulz, S., Schulze, J., Simonetti, S., Singh, J., Sitnik, K. M., Stark, R., Starossom, S., Stehle, C., Szelinski, F., Tan, L., Tarnok, A., Tornack, J., Tree, T. I. M., van Beek, J. J. P., van de Veen, W., van Gisbergen, K., Vasco, C., Verheyden, N. A., von Borstel, A., Ward-Hartstonge, K. A., Warnatz, K., Waskow, C., Wiedemann, A., Wilharm, A., Wing, J., Wirz, O., Wittner, J., Yang, J. H. M., and Yang, J.

Subjects
Immunology, citometry, Flow Cytometry, Infections, ddc, Autoimmune Diseases, Animals, Chronic Disease, Humans, Mice, Neoplasms, Practice Guidelines as Topic, Immunology and Allergy, ddc:610, Function and Dysfunction of the Nervous System, guideline
Abstract

© 2021 The Authors., The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers., Hyun-Dong Chang is supported by the Dr. Rolf M. Schwiete Foundation. Susanne Melzer and Attila Tarnok thank De Novo Software for providing FCS Express. Enrico Lugli is supported by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC IG20676). Gabriele De Simone and Giovanni Galletti were supported by Fellowships from the Fondazione Italiana per la Ricerca sul Cancro-Associazione Italiana per la Ricerca sul Cancro (FIRC-AIRC). Jun Dong is supported by Deutsche Forschungsgemeinschft (DFG, German Research Foundation) Projektnummer 389687267 and Chinesisch-Deutsches Zentrum für Wissenschaftsförderung [Sino-German Center for Research Promotion (SGC)] grant C-0072. Nicola Gagliani, Samuel Huber and Franziska Muscate are supported by DFG fundings: SFB841,GA 2441/3-1, HU 1714/10-1. The tetramer APC-conjugated H-2K (d) HIV-1 gag197-205 AMQMLKETI used in TDS assay for mouse blood T cells was obtained through the NIH Tetramer Facility. Larissa Nogueira Almeida was supported by DFG research grant MA 2273/14-1. Supported by the following grants: AIRC 5X1000 2018 id. 21147 (Lorenzo Moretta); AIRC IG 2017 id. 19920 (Lorenzo Moretta); RC-2020 OPBG (Lorenzo Moretta); AIRC and European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 800924 (Linda Quatrini). Dirk Baumjohann was supported by Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Emmy Noether Programme BA 5132/1-2 (252623821) and Germany's Excellence Strategy EXC2151 (390873048).

Published
2021

41. Novel biomarkers for primary biliary cholangitis to improve diagnosis and understand underlying regulatory mechanisms

Author

Pietro Invernizzi, Alessio Gerussi, Luigi Muratori, Anna Torri, Sergio Abrignani, Antonia Sinisi, Jens Geginat, Mariacristina Crosti, Francesca Bernuzzi, Donatella Carpi, Monica Moro, Chiara Cordiglieri, Elisa Pesce, Renata Grifantini, Mauro Bombaci, Manuela Lanzafame, Luigi Terracciano, Bombaci, M, Pesce, E, Torri, A, Carpi, D, Crosti, M, Lanzafame, M, Cordiglieri, C, Sinisi, A, DEL MORO, L, Bernuzzi, F, Gerussi, A, Geginat, J, Muratori, L, Terracciano, L, Invernizzi, P, Abrignani, S, Grifantini, R, Bombaci M., Pesce E., Torri A., Carpi D., Crosti M., Lanzafame M., Cordiglieri C., Sinisi A., Moro M., Bernuzzi F., Gerussi A., Geginat J., Muratori L., Terracciano L.M., Invernizzi P., Abrignani S., and Grifantini R.

Subjects
Adult, Male, Cirrhosis, Hepatitis C virus, Autoimmune hepatitis, medicine.disease_cause, Autoantigens, primary biliary cholangiti, Serology, Primary sclerosing cholangitis, Biliary disease, 03 medical and health sciences, Young Adult, GARP, 0302 clinical medicine, medicine, Humans, protein array, Aged, Autoantibodies, Aged, 80 and over, Hepatology, business.industry, Liver Cirrhosis, Biliary, Membrane Proteins, Middle Aged, medicine.disease, Cryoglobulinemia, Mitochondria, liver autoimmune disease, 030220 oncology & carcinogenesis, Immunology, biomarker, Biomarker (medicine), 030211 gastroenterology & hepatology, Female, business, Biomarkers
Abstract

Background and aims: Primary biliary cholangitis is an autoimmune biliary disease characterized by injury of bile ducts, eventually leading to cirrhosis and death. In most cases, anti-mitochondrial antibodies and persistently elevated serum alkaline phosphatase are the basis for the serological diagnosis.Anti-nuclear antibodies are also useful and may indicate a more aggressive diseases course. In patients in which anti-mitochondrial antibodies are not detected, an accurate diagnosis requires liver histology. This study aims at identifying specific biomarkers for the serological diagnosis of primary biliary cholangitis. Methods: Sera from patients affected by primary biliary cholangitis, primary sclerosing cholangitis, hepatitis C virus (with and without cryoglobulinemia), hepatocarcinoma and healthy donors were tested on a protein array representing 1658 human proteins. The most reactive autoantigens were confirmed by DELFIA analysis on expanded cohorts of the same mentioned serum classes, and on autoimmune hepatitis sera, using anti-PDC-E2 as reference biomarker. Results: Two autoantigens, SPATA31A3 and GARP, showed high reactivity with primary biliary cholangitis sera, containing or not anti-mitochondrial antibodies. Their combination with PDC-E2 allowed to discriminate primary biliary cholangitis from all tested control classes with high sensitivity and specificity. We found that GARP expression is upregulated upon exposure to biliary salts in human cholangiocytes, an event involving EGFR and insulin pathways. GARP expression was also detected in biliary duct cells of PBC patients. Conclusions: This study highlighted SPATA31A3 and GARP as new biomarkers for primary biliary cholangitis and unravelled molecular stimuli underlying GARP expression in human cholangiocytes.

Published
2019

42. Regulatory T-cell-derived interleukin-15 shapes cytotoxic T cell memory

Author

Jens Geginat, Francesca Granucci, Geginat, J, and Granucci, F

Subjects
Immunology, Immunology and Allergy, regulatory T cells ⋅ IL-15 ⋅ FOXP3 ⋅ CD8+ memory T cell
Abstract

It is well known that regulatory T-cells (Tregs) are required to prevent autoimmunity, but they may also have some less-well understood immune-stimulatory effects. In particular, in CD8(+) T-cell responses Tregs select high-affinity clones upon priming and promote memory by inhibiting inflammation-dependent generation of short-lived effector cells. In the current issue of the European Journal of Immunology [Eur. J. Immunol. 2023. 53: XXXX-XXXX], Madi et al. report the surprising finding that human and murine FOXP3(+) Tregs are a physiologically relevant source of IL-15, a homeostatic cytokine that promotes antigen-independent maintenance of CD8(+) memory T-cells. In mice that lack IL-15 selectively in FOXP3(+)Tregs the authors show that the composition of the CD8(+) T-cell memory pool is altered in the absence of Treg-derived IL-15, since a subset of terminally effector memory cells is drastically reduced. Otherwise Treg-derived IL-15 is dispensable for antiviral immune responses and the generation of anti-viral CD8(+) memory T-cells. These findings add to our understanding of the multifaceted role of Tregs in immune responses, and how IL-15 derived from different cellular sources maintains anti-viral T-cell memory.

Published
2022

43. Clonally expanded EOMES+ Tr1-like cells in primary and metastatic tumors are associated with disease progression

Author

Salvatore Siena, Emilia Maria Cristina Mazza, Giulia Della Chiara, Chiara Godano, Nicola Zucchini, Valeria Ranzani, Stefania Oliveto, Paola Gruarin, Jens Geginat, Roberto Bosotti, Claudia D'Oria, Elena Carelli, Pierluigi Novellis, Saveria Mazzara, Ylenia Silvestri, Marco Passaro, Alessio Amatu, Marco Alloisio, Antonio Lanzavecchia, Stefano Biffo, Giorgia Alvisi, Federica Gervasoni, Maria Lucia Sarnicola, N. Mariani, Alberto Bardelli, Ramona Bason, Jolanda Brummelman, Mariangela Lorenzo, Giulia Veronesi, Emanuela Bonoldi, Massimiliano Pagani, Daniele Prati, Enrico Opocher, Lorenzo Drufuca, Martina Martinovic, Andrea Sartore-Bianchi, Sergio Abrignani, Alessandro Giani, Marco De Simone, Enrico Lugli, Chiara Cordiglieri, Serena Curti, Grazisa Rossetti, Valeria Bevilacqua, Andrea Pisani Ceretti, Raoul J. P. Bonnal, Bonnal, R. J. P., Rossetti, G., Lugli, E., De Simone, M., Gruarin, P., Brummelman, J., Drufuca, L., Passaro, M., Bason, R., Gervasoni, F., Della Chiara, G., D'Oria, C., Martinovic, M., Curti, S., Ranzani, V., Cordiglieri, C., Alvisi, G., Mazza, E. M. C., Oliveto, S., Silvestri, Y., Carelli, E., Mazzara, S., Bosotti, R., Sarnicola, M. L., Godano, C., Bevilacqua, V., Lorenzo, M., Siena, S., Bonoldi, E., Sartore-Bianchi, A., Amatu, A., Veronesi, G., Novellis, P., Alloisio, M., Giani, A., Zucchini, N., Opocher, E., Ceretti, A. P., Mariani, N., Biffo, S., Prati, D., Bardelli, A., Geginat, J., Lanzavecchia, A., Abrignani, S., and Pagani, M.

Subjects
Male, 0301 basic medicine, Lung Neoplasms, T-Lymphocytes, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], medicine.medical_treatment, Programmed Cell Death 1 Receptor, Drug Resistance, Datasets as Topic, Kaplan-Meier Estimate, Granzymes, 0302 clinical medicine, Cancer immunotherapy, Single-cell analysis, 80 and over, Immunology and Allergy, RNA-Seq, Non-Small-Cell Lung, Immune Checkpoint Inhibitors, Adjuvant, Colectomy, Chitinases, Cell Differentiation, Forkhead Transcription Factors, Middle Aged, Flow Cytometry, Regulatory, Adult, Aged, Aged, 80 and over, Carcinoma, Non-Small-Cell Lung, Cell Proliferation, Chemotherapy, Adjuvant, Clonal Hematopoiesis, Colon, Colorectal Neoplasms, Disease Progression, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Primary Cell Culture, Single-Cell Analysis, T-Box Domain Proteins, T-Lymphocytes, Regulatory, Immunology, Biology, 03 medical and health sciences, Immune system, medicine, Chemotherapy, Neoplastic, Carcinoma, Immunotherapy, 030104 developmental biology, Gene Expression Regulation, Cell culture, Cancer research, Neoplasm, Granzyme K, Eomesodermin Homolog, Checkpoint Blockade Immunotherapy, 030215 immunology
Abstract

Regulatory T (Treg) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4+ T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3+ Treg and eomesodermin homolog (EOMES)+ type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES+ Tr1-like cells, but not Treg cells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES+ Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1–targeted immunotherapy. Collectively, these findings highlight the heterogeneity of Treg cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy. Human primary and metastatic tumors harbor CD4+ Treg cells that can suppress antitumor immune responses. Bonnal et al. identify an intratumoral type 1 Treg-like CD4+ T cell subset that expresses the transcription factor EOMES, granzyme K and CHI3L2. This EOMES+ T cell subset correlates with disease progression but is responsive to PD-1 checkpoint blockade immunotherapy.

Published
2021

44. Ex vivo microRNA and gene expression profiling of human Tr1-like cells suggests a role for miR-92a and -125a in the regulation of EOMES and IL-10R

Author

Maria Cristina Crosti, Marco De Simone, Saveria Mazzara, Valeria Ranzani, Jens Geginat, Grazisa Rossetti, Giorgia Moschetti, Sergio Abrignani, Paola Gruarin, Michele Chirichella, Massimiliano Pagani, Stefan Emming, Silvia Monticelli, Stefano Maglie, Chiara Vasco, Nadia Pulvirenti, De Simone, M, Chirichella, M, Emming, S, Mazzara, S, Ranzani, V, Gruarin, P, Moschetti, G, Pulvirenti, N, Maglie, S, Vasco, C, Crosti, M, Rossetti, G, Pagani, M, Abrignani, S, Monticelli, S, and Geginat, J

Subjects
genetic structures, microRNA, Gene Expression Profiling, Immunology, Biology, Th1 Cells, BIO/11 - BIOLOGIA MOLECOLARE, eye diseases, Cell biology, Tr1-like cell, Gene expression profiling, MicroRNAs, Gene expression, EOMES, Immunology and Allergy, Cytotoxic T cell, Mirna profiling, Humans, Receptors, Interleukin-10, sense organs, T-Box Domain Proteins, Ex vivo, IL-10R
Abstract

Ex vivo gene expression and miRNA profiling of Eomes+ Tr1-like cells suggested that they represent a differentiation stage that is intermediate between Th1-cells and cytotoxic CD4+ T-cells. Several microRNAs were downregulated in Eomes+ Tr1-like cells that might inhibit Tr1-cell differentiation. In particular, miR-92a targeted Eomes, while miR-125a inhibited IFN-g and IL-10R expression.

Published
2021

45. Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Author

Lara Gibellini, Sussan Nourshargh, Susanna Cardell, Wlodzimierz Maslinski, Mar Felipo-Benavent, Florian Mair, Hans-Martin Jäck, Lilly Lopez, Klaus Warnatz, John Trowsdale, Diana Ordonez, Marcus Eich, William Hwang, Anne Cooke, Dirk Mielenz, Alberto Orfao, Winfried F. Pickl, Vladimir Benes, Alice Yue, T. Vincent Shankey, Maria Tsoumakidou, Virginia Litwin, Gelo Victoriano Dela Cruz, Andrea Cavani, Sara De Biasi, Larissa Nogueira Almeida, Jonathan J M Landry, Claudia Haftmann, Charlotte Esser, Ana Cumano, Anneke Wilharm, Francesco Dieli, Rudi Beyaert, Alessio Mazzoni, Burkhard Ludewig, Carlo Pucillo, Dirk H. Busch, Joe Trotter, Stipan Jonjić, Marc Veldhoen, Josef Spidlen, Aja M. Rieger, Dieter Adam, Srijit Khan, Todd A. Fehniger, Giuseppe Matarese, Maximilien Evrard, Christian Maueröder, Steffen Schmitt, Kristin A. Hogquist, Barry Moran, Raghavendra Palankar, Markus Feuerer, S Schmid, Susann Rahmig, Amy E. Lovett-Racke, James V. Watson, Megan K. Levings, Susanne Melzer, Dinko Pavlinic, Christopher M. Harpur, Christina Stehle, A. Graham Pockley, Toshinori Nakayama, Attila Tárnok, Juhao Yang, Michael Lohoff, Paulo Vieira, Francisco Sala-de-Oyanguren, Christian Kurts, Anastasia Gangaev, Alfonso Blanco, Hans Scherer, Regine J. Dress, Bruno Silva-Santos, Kiyoshi Takeda, Bimba F. Hoyer, Ilenia Cammarata, Daryl Grummitt, Isabel Panse, Günnur Deniz, Bianka Baying, Friederike Ebner, Esther Schimisky, Leo Hansmann, Thomas Kamradt, Edwin van der Pol, Daniel Scott-Algara, Anna Iannone, Giorgia Alvisi, Sebastian R. Schulz, Francesco Liotta, Irmgard Förster, Beatriz Jávega, Hans-Peter Rahn, Caetano Reis e Sousa, Livius Penter, Xuetao Cao, David P. Sester, Keisuke Goda, Peter Wurst, Iain B. McInnes, Ricardo T. Gazzinelli, Federica Piancone, Gerald Willimsky, Yotam Raz, Pärt Peterson, Wolfgang Fritzsche, Yvonne Samstag, Martin Büscher, Thomas Schüler, Susanne Hartmann, Robert J. Wilkinson, Anna E. S. Brooks, Steven L. C. Ketelaars, Catherine Sautès-Fridman, Anna Rubartelli, Petra Bacher, Katja Kobow, Marco A. Cassatella, Andrea Hauser, Henrik E. Mei, Kilian Schober, Silvia Della Bella, Graham Anderson, Michael D. Ward, Garth Cameron, Sebastian Lunemann, Katharina Kriegsmann, Katarzyna M. Sitnik, Brice Gaudilliere, Chantip Dang-Heine, Marcello Pinti, Paul Klenerman, Frank A. Schildberg, Joana Barros-Martins, Laura G. Rico, Hanlin Zhang, Christian Münz, Thomas Dörner, Jakob Zimmermann, Andrea M. Cooper, Jonni S. Moore, Andreas Diefenbach, Yanling Liu, Wolfgang Bauer, Tobit Steinmetz, Katharina Pracht, Leonard Tan, Peter K. Jani, Alan M. Stall, Petra Hoffmann, Christine S. Falk, Jasmin Knopf, Simon Fillatreau, Hans-Dieter Volk, Luis E. Muñoz, David L. Haviland, William W. Agace, Jonathan Rebhahn, Ljiljana Cvetkovic, Mohamed Trebak, Jordi Petriz, Mario Clerici, Diether J. Recktenwald, Anders Ståhlberg, Tristan Holland, Helen M. McGuire, Sa A. Wang, Christian Kukat, Thomas Kroneis, Laura Cook, Wan Ting Kong, Xin M. Wang, Britta Engelhardt, Pierre Coulie, Genny Del Zotto, Sally A. Quataert, Kata Filkor, Gabriele Multhoff, Bartek Rajwa, Federica Calzetti, Hans Minderman, Cosima T. Baldari, Jens Geginat, Hervé Luche, Gert Van Isterdael, Linda Schadt, Sophia Urbanczyk, Giovanna Borsellino, Liping Yu, Dale I. Godfrey, Achille Anselmo, Rachael C. Walker, Andreas Grützkau, David W. Hedley, Birgit Sawitzki, Silvia Piconese, Maria Yazdanbakhsh, Burkhard Becher, Ramon Bellmas Sanz, Michael Delacher, Hyun-Dong Chang, Immanuel Andrä, Hans-Gustaf Ljunggren, José-Enrique O'Connor, Ahad Khalilnezhad, Sharon Sanderson, Federico Colombo, Götz R. A. Ehrhardt, Inga Sandrock, Enrico Lugli, Christian Bogdan, James B. Wing, Susann Müller, Tomohiro Kurosaki, Derek Davies, Ester B. M. Remmerswaal, Kylie M. Quinn, Christopher A. Hunter, Andreas Radbruch, Timothy P. Bushnell, Anna Erdei, Sabine Adam-Klages, Pascale Eede, Van Duc Dang, Rieke Winkelmann, Thomas Korn, Gemma A. Foulds, Dirk Baumjohann, Matthias Schiemann, Manfred Kopf, Jan Kisielow, Lisa Richter, Jochen Huehn, Gloria Martrus, Alexander Scheffold, Jessica G. Borger, Sidonia B G Eckle, John Bellamy Foster, Anna Katharina Simon, Alicia Wong, Mübeccel Akdis, Gisa Tiegs, Toralf Kaiser, James McCluskey, Anna Vittoria Mattioli, Aaron J. Marshall, Hui-Fern Koay, Eva Orlowski-Oliver, Anja E. Hauser, J. Paul Robinson, Jay K. Kolls, Luca Battistini, Mairi McGrath, Jane L. Grogan, Natalio Garbi, Timothy Tree, Kingston H. G. Mills, Stefan H. E. Kaufmann, Wolfgang Schuh, Ryan R. Brinkman, Tim R. Mosmann, Vincenzo Barnaba, Andreas Dolf, Lorenzo Cosmi, Bo Huang, Andreia C. Lino, Baerbel Keller, René A. W. van Lier, Alexandra J. Corbett, Paul S. Frenette, Pleun Hombrink, Helena Radbruch, Sofie Van Gassen, Olivier Lantz, Lorenzo Moretta, Désirée Kunkel, Kirsten A. Ward-Hartstonge, Armin Saalmüller, Leslie Y. T. Leung, Salvador Vento-Asturias, Paola Lanuti, Alicia Martínez-Romero, Sarah Warth, Zhiyong Poon, Diana Dudziak, Andrea Cossarizza, Kovit Pattanapanyasat, Konrad von Volkmann, Jessica P. Houston, Agnès Lehuen, Andrew Filby, Pratip K. Chattopadhyay, Stefano Casola, Annika Wiedemann, Hannes Stockinger, Jürgen Ruland, Arturo Zychlinsky, Claudia Waskow, Katrin Neumann, Ari Waisman, Lucienne Chatenoud, Sudipto Bari, Kamran Ghoreschi, David W. Galbraith, Yvan Saeys, Hamida Hammad, Andrea Gori, Miguel López-Botet, Gabriel Núñez, Sabine Ivison, Michael Hundemer, Dorothea Reimer, Mark C. Dessing, Günter J. Hämmerling, Rudolf A. Manz, Tomas Kalina, Jonas Hahn, Holden T. Maecker, Hendy Kristyanto, Martin S. Davey, Henning Ulrich, Michael L. Dustin, Takashi Saito, Yousuke Takahama, Milena Nasi, Johanna Huber, Jürgen Wienands, Paolo Dellabona, Andreas Schlitzer, Michael D. Leipold, Kerstin H. Mair, Christian Peth, Immo Prinz, Chiara Romagnani, José M. González-Navajas, Josephine Schlosser, Marina Saresella, Matthias Edinger, Dirk Brenner, Nicole Baumgarth, Rikard Holmdahl, Fang-Ping Huang, Guadalupe Herrera, Malte Paulsen, Gergely Toldi, Luka Cicin-Sain, Reiner Schulte, Christina E. Zielinski, Thomas Winkler, Christoph Goettlinger, Philip E. Boulais, Jennie H M Yang, Antonio Celada, Heike Kunze-Schumacher, Julia Tornack, Florian Ingelfinger, Jenny Mjösberg, Andy Riddell, Leonie Wegener, Thomas Höfer, Christoph Hess, James P. Di Santo, Anna E. Oja, J. Kühne, Willem van de Veen, Mary Bebawy, Alberto Mantovani, Bart Everts, Giovanna Lombardi, Laura Maggi, Anouk von Borstel, Pia Kvistborg, Elisabetta Traggiai, A Ochel, Nima Aghaeepour, Charles-Antoine Dutertre, Matthieu Allez, Thomas Höllt, Wenjun Ouyang, Regina Stark, Maries van den Broek, Shimon Sakaguchi, Paul K. Wallace, Silvano Sozzani, Francesca LaRosa, Annette Oxenius, Malgorzata J. Podolska, Ivana Marventano, Wilhelm Gerner, Oliver F. Wirz, Britta Frehse, Gevitha Ravichandran, Martin Herrmann, Carl S. Goodyear, Gary Warnes, Helen Ferry, Stefan Frischbutter, Tim R. Radstake, Salomé LeibundGut-Landmann, Yi Zhao, Axel Schulz, Angela Santoni, Pablo Engel, Daniela C. Hernández, Andreas Acs, Cristiano Scottà, Francesco Annunziato, Thomas Weisenburger, Wolfgang Beisker, Sue Chow, Fritz Melchers, Daniel E. Speiser, Immanuel Kwok, Florent Ginhoux, Dominic A. Boardman, Natalie Stanley, Carsten Watzl, Marie Follo, Erik Lubberts, Andreas Krueger, Susanne Ziegler, Göran K. Hansson, David Voehringer, Antonia Niedobitek, Eleni Christakou, Lai Guan Ng, Sabine Baumgart, Nicholas A Gherardin, Antonio Cosma, Orla Maguire, Jolene Bradford, Daniel Schraivogel, Linda Quatrini, Stephen D. Miller, Rheumatology, Università degli Studi di Modena e Reggio Emilia (UNIMORE), Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, Swiss Institute of Allergy and Asthma Research (SIAF), Universität Zürich [Zürich] = University of Zurich (UZH), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Internal Medicine, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI)-DENOTHE Center, Institute of Clinical Molecular Biology, Kiel University, Department of Life Sciences [Siena, Italy], Università degli Studi di Siena = University of Siena (UNISI), Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP), Dulbecco Telethon Institute/Department of Biology, Caprotec Bioanalytics GmbH, International Occultation Timing Association European Section (IOTA ES), International Occultation Timing Association European Section, European Molecular Biology Laboratory [Heidelberg] (EMBL), VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Fondazione Santa Lucia (IRCCS), Department of Immunology, Chinese Academy of Medical Sciences, FIRC Institute of Molecular Oncology Foundation, IFOM, Istituto FIRC di Oncologia Molecolare (IFOM), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Physiopatology and Transplantation, University of Milan (DEPT), University of Milan, Monash University [Clayton], Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institute of Cellular Pathology, Université Catholique de Louvain = Catholic University of Louvain (UCL), Lymphopoïèse (Lymphopoïèse (UMR_1223 / U1223 / U-Pasteur_4)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Experimental Immunology Unit, Dept. of Oncology, DIBIT San Raffaele Scientific Institute, Immunité Innée - Innate Immunity, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biopharmacy [Bruxelles, Belgium] (Institute for Medical Immunology IMI), Université libre de Bruxelles (ULB), Charité Hospital, Humboldt-Universität zu Berlin, Agency for science, technology and research [Singapore] (A*STAR), Laboratory of Molecular Immunology and the Howard Hughes Institute, Rockefeller University [New York], Kennedy Institute of Rheumatology [Oxford, UK], Imperial College London, Theodor Kocher Institute, University of Bern, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] ( IUF), Université Lumière - Lyon 2 (UL2), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), University of Edinburgh, Integrative Biology Program [Milano], Istituto Nazionale Genetica Molecolare [Milano] (INGM), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Universitat de Barcelona (UB), Rheumatologie, Cell Biology, Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Department for Internal Medicine 3, Institute for Clinical Immunology, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Delft University of Technology (TU Delft), Medical Inflammation Research, Karolinska Institutet [Stockholm], Department of Photonics Engineering [Lyngby], Technical University of Denmark [Lyngby] (DTU), Dpt of Experimental Immunology [Braunschweig], Helmholtz Centre for Infection Research (HZI), Department of Internal Medicine V, Universität Heidelberg [Heidelberg], Department of Histology and Embryology, University of Rijeka, Freiburg University Medical Center, Nuffield Dept of Clinical Medicine, University of Oxford [Oxford]-NIHR Biomedical Research Centre, Institute of Integrative Biology, Molecular Biomedicine, Berlin Institute of Health (BIH), Laboratory for Lymphocyte Differentiation, RIKEN Research Center, Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Department of Surgery [Vancouver, BC, Canada] (Child and Family Research Institute), University of British Columbia (UBC)-Child and Family Research Institute [Vancouver, BC, Canada], College of Food Science and Technology [Shangai], Shanghai Ocean University, Institute for Medical Microbiology and Hygiene, University of Marburg, King‘s College London, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre d'Immunophénomique (CIPHE), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Brustzentrum Kantonsspital St. Gallen, Immunotechnology Section, Vaccine Research Center, National Institutes of Health [Bethesda] (NIH)-National Institute of Allergy and Infectious Diseases, Heinrich Pette Institute [Hamburg], Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Department of Immunology and Cell Biology, Mario Negri Institute, Laboratory of Molecular Medicine and Biotechnology, Don C. Gnocchi ONLUS Foundation, Institute of Translational Medicine, Klinik für Dermatologie, Venerologie und Allergologie, School of Biochemistry and Immunology, Department of Medicine Huddinge, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm]-Lipid Laboratory, Università di Genova, Dipartimento di Medicina Sperimentale, Department of Environmental Microbiology, Helmholtz Zentrum für Umweltforschung = Helmholtz Centre for Environmental Research (UFZ), Department of Radiation Oncology [Munich], Ludwig-Maximilians-Universität München (LMU), Centre de Recherche Publique- Santé, Université du Luxembourg (Uni.lu), William Harvey Research Institute, Barts and the London Medical School, University of Michigan [Ann Arbor], University of Michigan System, Centro de Investigacion del Cancer (CSIC), Universitario de Salamanca, Molecular Pathology [Tartu, Estonia], University of Tartu, Hannover Medical School [Hannover] (MHH), Centre d'Immunologie de Marseille - Luminy (CIML), Monash Biomedicine Discovery Institute, Cytometry Laboratories and School of Veterinary Medicine, Purdue University [West Lafayette], Data Mining and Modelling for Biomedicine [Ghent, Belgium], VIB Center for Inflammation Research [Ghent, Belgium], Laboratory for Cell Signaling, RIKEN Research Center for Allergy and Immunology, RIKEN Research Center for Allergy and Immunology, Osaka University [Osaka], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Institute of Medical Immunology [Berlin, Germany], FACS and Array Core Facility, Johannes Gutenberg - Universität Mainz (JGU), Otto-von-Guericke University [Magdeburg] (OVGU), SUPA School of Physics and Astronomy [University of St Andrews], University of St Andrews [Scotland]-Scottish Universities Physics Alliance (SUPA), Biologie Cellulaire des Lymphocytes - Lymphocyte Cell Biology, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), General Pathology and Immunology (GPI), University of Brescia, Université de Lausanne (UNIL), Terry Fox Laboratory, BC Cancer Agency (BCCRC)-British Columbia Cancer Agency Research Centre, Department of Molecular Immunology, Medizinische Universität Wien = Medical University of Vienna, Dept. Pediatric Cardiology, Universität Leipzig [Leipzig], Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Cardiovascular Sciences, Albany Medical College, Dept Pathol, Div Immunol, University of Cambridge [UK] (CAM), Department of Information Technology [Gent], Universiteit Gent, Department of Plant Systems Biology, Department of Plant Biotechnology and Genetics, Universiteit Gent = Ghent University [Belgium] (UGENT), Division of Molecular Immunology, Institute for Immunology, Department of Geological Sciences, University of Oregon [Eugene], Centers for Disease Control and Prevention [Atlanta] (CDC), Centers for Disease Control and Prevention, University of Colorado [Colorado Springs] (UCCS), FACS laboratory, Cancer Research, London, Cancer Research UK, Regeneration in Hematopoiesis and Animal Models of Hematopoiesis, Faculty of Medicine, Dresden University of Technology, Barbara Davis Center for Childhood Diabetes (BDC), University of Colorado Anschutz [Aurora], School of Computer and Electronic Information [Guangxi University], Guangxi University [Nanning], School of Materials Science and Engineering, Nanyang Technological University [Singapour], Max Planck Institute for Infection Biology (MPIIB), Max-Planck-Gesellschaft, Work in the laboratory of Dieter Adam is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—Projektnummer 125440785 – SFB 877, Project B2.Petra Hoffmann, Andrea Hauser, and Matthias Edinger thank BD Biosciences®, San José, CA, USA, and SKAN AG, Bale, Switzerland for fruitful cooperation during the development, construction, and installation of the GMP‐compliant cell sorting equipment and the Bavarian Immune Therapy Network (BayImmuNet) for financial support.Edwin van der Pol and Paola Lanuti acknowledge Aleksandra Gąsecka M.D. for excellent experimental support and Dr. Rienk Nieuwland for textual suggestions. This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO‐TTW), research program VENI 15924.Jessica G Borger, Kylie M Quinn, Mairi McGrath, and Regina Stark thank Francesco Siracusa and Patrick Maschmeyer for providing data.Larissa Nogueira Almeida was supported by DFG research grant MA 2273/14‐1. Rudolf A. Manz was supported by the Excellence Cluster 'Inflammation at Interfaces' (EXC 306/2).Susanne Hartmann and Friederike Ebner were supported by the German Research Foundation (GRK 2046).Hans Minderman was supported by NIH R50CA211108.This work was funded by the Deutsche Forschungsgemeinschaft through the grant TRR130 (project P11 and C03) to Thomas H. Winkler.Ramon Bellmàs Sanz, Jenny Kühne, and Christine S. Falk thank Jana Keil and Kerstin Daemen for excellent technical support. The work was funded by the Germany Research Foundation CRC738/B3 (CSF).The work by the Mei laboratory was supported by German Research Foundation Grant ME 3644/5‐1 and TRR130 TP24, the German Rheumatism Research Centre Berlin, European Union Innovative Medicines Initiative ‐ Joint Undertaking ‐ RTCure Grant Agreement 777357, the Else Kröner‐Fresenius‐Foundation, German Federal Ministry of Education and Research e:Med sysINFLAME Program Grant 01ZX1306B and KMU‐innovativ 'InnoCyt', and the Leibniz Science Campus for Chronic Inflammation (http://www.chronische-entzuendung.org).Axel Ronald Schulz, Antonio Cosma, Sabine Baumgart, Brice Gaudilliere, Helen M. McGuire, and Henrik E. Mei thank Michael D. Leipold for critically reading the manuscript.Christian Kukat acknowledges support from the ISAC SRL Emerging Leaders program.John Trowsdale received funding from the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant Agreement 695551)., European Project: 7728036(1978), Università degli Studi di Modena e Reggio Emilia = University of Modena and Reggio Emilia (UNIMORE), Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Università degli Studi di Firenze = University of Florence (UniFI)-DENOTHE Center, Università degli Studi di Milano = University of Milan (UNIMI), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Humboldt University Of Berlin, Leibniz Research Institute for Environmental Medicine [Düsseldorf, Germany] (IUF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Universität Heidelberg [Heidelberg] = Heidelberg University, Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), University of Oxford-NIHR Biomedical Research Centre, Universität Bonn = University of Bonn, Università degli Studi di Firenze = University of Florence (UniFI), Università degli studi di Genova = University of Genoa (UniGe), Universidad de Salamanca, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University (JGU), Otto-von-Guericke-Universität Magdeburg = Otto-von-Guericke University [Magdeburg] (OVGU), Université de Lausanne = University of Lausanne (UNIL), Universität Leipzig, Universiteit Gent = Ghent University (UGENT), HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., Cossarizza, A., Chang, H. -D., Radbruch, A., Acs, A., Adam, D., Adam-Klages, S., Agace, W. W., Aghaeepour, N., Akdis, M., Allez, M., Almeida, L. N., Alvisi, G., Anderson, G., Andra, I., Annunziato, F., Anselmo, A., Bacher, P., Baldari, C. T., Bari, S., Barnaba, V., Barros-Martins, J., Battistini, L., Bauer, W., Baumgart, S., Baumgarth, N., Baumjohann, D., Baying, B., Bebawy, M., Becher, B., Beisker, W., Benes, V., Beyaert, R., Blanco, A., Boardman, D. A., Bogdan, C., Borger, J. G., Borsellino, G., Boulais, P. E., Bradford, J. A., Brenner, D., Brinkman, R. R., Brooks, A. E. S., Busch, D. H., Buscher, M., Bushnell, T. P., Calzetti, F., Cameron, G., Cammarata, I., Cao, X., Cardell, S. L., Casola, S., Cassatella, M. A., Cavani, A., Celada, A., Chatenoud, L., Chattopadhyay, P. K., Chow, S., Christakou, E., Cicin-Sain, L., Clerici, M., Colombo, F. S., Cook, L., Cooke, A., Cooper, A. M., Corbett, A. J., Cosma, A., Cosmi, L., Coulie, P. G., Cumano, A., Cvetkovic, L., Dang, V. D., Dang-Heine, C., Davey, M. S., Davies, D., De Biasi, S., Del Zotto, G., Dela Cruz, G. V., Delacher, M., Della Bella, S., Dellabona, P., Deniz, G., Dessing, M., Di Santo, J. P., Diefenbach, A., Dieli, F., Dolf, A., Dorner, T., Dress, R. J., Dudziak, D., Dustin, M., Dutertre, C. -A., Ebner, F., Eckle, S. B. G., Edinger, M., Eede, P., Ehrhardt, G. R. A., Eich, M., Engel, P., Engelhardt, B., Erdei, A., Esser, C., Everts, B., Evrard, M., Falk, C. S., Fehniger, T. A., Felipo-Benavent, M., Ferry, H., Feuerer, M., Filby, A., Filkor, K., Fillatreau, S., Follo, M., Forster, I., Foster, J., Foulds, G. A., Frehse, B., Frenette, P. S., Frischbutter, S., Fritzsche, W., Galbraith, D. W., Gangaev, A., Garbi, N., Gaudilliere, B., Gazzinelli, R. T., Geginat, J., Gerner, W., Gherardin, N. A., Ghoreschi, K., Gibellini, L., Ginhoux, F., Goda, K., Godfrey, D. I., Goettlinger, C., Gonzalez-Navajas, J. M., Goodyear, C. S., Gori, A., Grogan, J. L., Grummitt, D., Grutzkau, A., Haftmann, C., Hahn, J., Hammad, H., Hammerling, G., Hansmann, L., Hansson, G., Harpur, C. M., Hartmann, S., Hauser, A., Hauser, A. E., Haviland, D. L., Hedley, D., Hernandez, D. C., Herrera, G., Herrmann, M., Hess, C., Hofer, T., Hoffmann, P., Hogquist, K., Holland, T., Hollt, T., Holmdahl, R., Hombrink, P., Houston, J. P., Hoyer, B. F., Huang, B., Huang, F. -P., Huber, J. E., Huehn, J., Hundemer, M., Hunter, C. A., Hwang, W. Y. K., Iannone, A., Ingelfinger, F., Ivison, S. M., Jack, H. -M., Jani, P. K., Javega, B., Jonjic, S., Kaiser, T., Kalina, T., Kamradt, T., Kaufmann, S. H. E., Keller, B., Ketelaars, S. L. C., Khalilnezhad, A., Khan, S., Kisielow, J., Klenerman, P., Knopf, J., Koay, H. -F., Kobow, K., Kolls, J. K., Kong, W. T., Kopf, M., Korn, T., Kriegsmann, K., Kristyanto, H., Kroneis, T., Krueger, A., Kuhne, J., Kukat, C., Kunkel, D., Kunze-Schumacher, H., Kurosaki, T., Kurts, C., Kvistborg, P., Kwok, I., Landry, J., Lantz, O., Lanuti, P., Larosa, F., Lehuen, A., LeibundGut-Landmann, S., Leipold, M. D., Leung, L. Y. T., Levings, M. K., Lino, A. C., Liotta, F., Litwin, V., Liu, Y., Ljunggren, H. -G., Lohoff, M., Lombardi, G., Lopez, L., Lopez-Botet, M., Lovett-Racke, A. E., Lubberts, E., Luche, H., Ludewig, B., Lugli, E., Lunemann, S., Maecker, H. T., Maggi, L., Maguire, O., Mair, F., Mair, K. H., Mantovani, A., Manz, R. A., Marshall, A. J., Martinez-Romero, A., Martrus, G., Marventano, I., Maslinski, W., Matarese, G., Mattioli, A. V., Maueroder, C., Mazzoni, A., Mccluskey, J., Mcgrath, M., Mcguire, H. M., Mcinnes, I. B., Mei, H. E., Melchers, F., Melzer, S., Mielenz, D., Miller, S. D., Mills, K. H. G., Minderman, H., Mjosberg, J., Moore, J., Moran, B., Moretta, L., Mosmann, T. R., Muller, S., Multhoff, G., Munoz, L. E., Munz, C., Nakayama, T., Nasi, M., Neumann, K., Ng, L. G., Niedobitek, A., Nourshargh, S., Nunez, G., O'Connor, J. -E., Ochel, A., Oja, A., Ordonez, D., Orfao, A., Orlowski-Oliver, E., Ouyang, W., Oxenius, A., Palankar, R., Panse, I., Pattanapanyasat, K., Paulsen, M., Pavlinic, D., Penter, L., Peterson, P., Peth, C., Petriz, J., Piancone, F., Pickl, W. F., Piconese, S., Pinti, M., Pockley, A. G., Podolska, M. J., Poon, Z., Pracht, K., Prinz, I., Pucillo, C. E. M., Quataert, S. A., Quatrini, L., Quinn, K. M., Radbruch, H., Radstake, T. R. D. J., Rahmig, S., Rahn, H. -P., Rajwa, B., Ravichandran, G., Raz, Y., Rebhahn, J. A., Recktenwald, D., Reimer, D., Reis e Sousa, C., Remmerswaal, E. B. M., Richter, L., Rico, L. G., Riddell, A., Rieger, A. M., Robinson, J. P., Romagnani, C., Rubartelli, A., Ruland, J., Saalmuller, A., Saeys, Y., Saito, T., Sakaguchi, S., Sala-de-Oyanguren, F., Samstag, Y., Sanderson, S., Sandrock, I., Santoni, A., Sanz, R. B., Saresella, M., Sautes-Fridman, C., Sawitzki, B., Schadt, L., Scheffold, A., Scherer, H. U., Schiemann, M., Schildberg, F. A., Schimisky, E., Schlitzer, A., Schlosser, J., Schmid, S., Schmitt, S., Schober, K., Schraivogel, D., Schuh, W., Schuler, T., Schulte, R., Schulz, A. R., Schulz, S. R., Scotta, C., Scott-Algara, D., Sester, D. P., Shankey, T. V., Silva-Santos, B., Simon, A. K., Sitnik, K. M., Sozzani, S., Speiser, D. E., Spidlen, J., Stahlberg, A., Stall, A. M., Stanley, N., Stark, R., Stehle, C., Steinmetz, T., Stockinger, H., Takahama, Y., Takeda, K., Tan, L., Tarnok, A., Tiegs, G., Toldi, G., Tornack, J., Traggiai, E., Trebak, M., Tree, T. I. M., Trotter, J., Trowsdale, J., Tsoumakidou, M., Ulrich, H., Urbanczyk, S., van de Veen, W., van den Broek, M., van der Pol, E., Van Gassen, S., Van Isterdael, G., van Lier, R. A. W., Veldhoen, M., Vento-Asturias, S., Vieira, P., Voehringer, D., Volk, H. -D., von Borstel, A., von Volkmann, K., Waisman, A., Walker, R. V., Wallace, P. K., Wang, S. A., Wang, X. M., Ward, M. D., Ward-Hartstonge, K. A., Warnatz, K., Warnes, G., Warth, S., Waskow, C., Watson, J. V., Watzl, C., Wegener, L., Weisenburger, T., Wiedemann, A., Wienands, J., Wilharm, A., Wilkinson, R. J., Willimsky, G., Wing, J. B., Winkelmann, R., Winkler, T. H., Wirz, O. F., Wong, A., Wurst, P., Yang, J. H. M., Yang, J., Yazdanbakhsh, M., Yu, L., Yue, A., Zhang, H., Zhao, Y., Ziegler, S. M., Zielinski, C., Zimmermann, J., Zychlinsky, A., UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/GECE - Génétique cellulaire, Netherlands Organization for Scientific Research, German Research Foundation, European Commission, European Research Council, Repositório da Universidade de Lisboa, CCA - Imaging and biomarkers, Experimental Immunology, AII - Infectious diseases, AII - Inflammatory diseases, Biomedical Engineering and Physics, ACS - Atherosclerosis & ischemic syndromes, and Landsteiner Laboratory

Subjects
0301 basic medicine, Consensus, Immunology, Consensu, Cell Separation, Biology, Article, Flow cytometry, 03 medical and health sciences, 0302 clinical medicine, Guidelines, Allergy and Immunology, medicine, Cell separation, Immunology and Allergy, Humans, guidelines, flow cytometry, immunology, medicine.diagnostic_test, BIOMEDICINE AND HEALTHCARE. Basic Medical Sciences, Cell sorting, Flow Cytometry, Cell selection, Data science, 3. Good health, 030104 developmental biology, Phenotype, [SDV.IMM]Life Sciences [q-bio]/Immunology, BIOMEDICINA I ZDRAVSTVO. Temeljne medicinske znanosti, 030215 immunology, Human
Abstract

All authors: Andrea Cossarizza Hyun‐Dong Chang Andreas Radbruch Andreas Acs Dieter Adam Sabine Adam‐Klages William W. Agace Nima Aghaeepour Mübeccel Akdis Matthieu Allez Larissa Nogueira Almeida Giorgia Alvisi Graham Anderson Immanuel Andrä Francesco Annunziato Achille Anselmo Petra Bacher Cosima T. Baldari Sudipto Bari Vincenzo Barnaba Joana Barros‐Martins Luca Battistini Wolfgang Bauer Sabine Baumgart Nicole Baumgarth Dirk Baumjohann Bianka Baying Mary Bebawy Burkhard Becher Wolfgang Beisker Vladimir Benes Rudi Beyaert Alfonso Blanco Dominic A. Boardman Christian Bogdan Jessica G. Borger Giovanna Borsellino Philip E. Boulais Jolene A. Bradford Dirk Brenner Ryan R. Brinkman Anna E. S. Brooks Dirk H. Busch Martin Büscher Timothy P. Bushnell Federica Calzetti Garth Cameron Ilenia Cammarata Xuetao Cao Susanna L. Cardell Stefano Casola Marco A. Cassatella Andrea Cavani Antonio Celada Lucienne Chatenoud Pratip K. Chattopadhyay Sue Chow Eleni Christakou Luka Čičin‐Šain Mario Clerici Federico S. Colombo Laura Cook Anne Cooke Andrea M. Cooper Alexandra J. Corbett Antonio Cosma Lorenzo Cosmi Pierre G. Coulie Ana Cumano Ljiljana Cvetkovic Van Duc Dang Chantip Dang‐Heine Martin S. Davey Derek Davies Sara De Biasi Genny Del Zotto Gelo Victoriano Dela Cruz Michael Delacher Silvia Della Bella Paolo Dellabona Günnur Deniz Mark Dessing James P. Di Santo Andreas Diefenbach Francesco Dieli Andreas Dolf Thomas Dörner Regine J. Dress Diana Dudziak Michael Dustin Charles‐Antoine Dutertre Friederike Ebner Sidonia B. G. Eckle Matthias Edinger Pascale Eede Götz R.A. Ehrhardt Marcus Eich Pablo Engel Britta Engelhardt Anna Erdei Charlotte Esser Bart Everts Maximilien Evrard Christine S. Falk Todd A. Fehniger Mar Felipo‐Benavent Helen Ferry Markus Feuerer Andrew Filby Kata Filkor Simon Fillatreau Marie Follo Irmgard Förster John Foster Gemma A. Foulds Britta Frehse Paul S. Frenette Stefan Frischbutter Wolfgang Fritzsche David W. Galbraith Anastasia Gangaev Natalio Garbi Brice Gaudilliere Ricardo T. Gazzinelli Jens Geginat Wilhelm Gerner Nicholas A. Gherardin Kamran Ghoreschi Lara Gibellini Florent Ginhoux Keisuke Goda Dale I. Godfrey Christoph Goettlinger Jose M. González‐Navajas Carl S. Goodyear Andrea Gori Jane L. Grogan Daryl Grummitt Andreas Grützkau Claudia Haftmann Jonas Hahn Hamida Hammad Günter Hämmerling Leo Hansmann Goran Hansson Christopher M. Harpur Susanne Hartmann Andrea Hauser Anja E. Hauser David L. Haviland David Hedley Daniela C. Hernández Guadalupe Herrera Martin Herrmann Christoph Hess Thomas Höfer Petra Hoffmann Kristin Hogquist Tristan Holland Thomas Höllt Rikard Holmdahl Pleun Hombrink Jessica P. Houston Bimba F. Hoyer Bo Huang Fang‐Ping Huang Johanna E. Huber Jochen Huehn Michael Hundemer Christopher A. Hunter William Y. K. Hwang Anna Iannone Florian Ingelfinger Sabine M Ivison Hans‐Martin Jäck Peter K. Jani Beatriz Jávega Stipan Jonjic Toralf Kaiser Tomas Kalina Thomas Kamradt Stefan H. E. Kaufmann Baerbel Keller Steven L. C. Ketelaars Ahad Khalilnezhad Srijit Khan Jan Kisielow Paul Klenerman Jasmin Knopf Hui‐Fern Koay Katja Kobow Jay K. Kolls Wan Ting Kong Manfred Kopf Thomas Korn Katharina Kriegsmann Hendy Kristyanto Thomas Kroneis Andreas Krueger Jenny Kühne Christian Kukat Désirée Kunkel Heike Kunze‐Schumacher Tomohiro Kurosaki Christian Kurts Pia Kvistborg Immanuel Kwok Jonathan Landry Olivier Lantz Paola Lanuti Francesca LaRosa Agnès Lehuen Salomé LeibundGut‐Landmann Michael D. Leipold Leslie Y.T. Leung Megan K. Levings Andreia C. Lino Francesco Liotta Virginia Litwin Yanling Liu Hans‐Gustaf Ljunggren Michael Lohoff Giovanna Lombardi Lilly Lopez Miguel López‐Botet Amy E. Lovett‐Racke Erik Lubberts Herve Luche Burkhard Ludewig Enrico Lugli Sebastian Lunemann Holden T. Maecker Laura Maggi Orla Maguire Florian Mair Kerstin H. Mair Alberto Mantovani Rudolf A. Manz Aaron J. Marshall Alicia Martínez‐Romero Glòria Martrus Ivana Marventano Wlodzimierz Maslinski Giuseppe Matarese Anna Vittoria Mattioli Christian Maueröder Alessio Mazzoni James McCluskey Mairi McGrath Helen M. McGuire Iain B. McInnes Henrik E. Mei Fritz Melchers Susanne Melzer Dirk Mielenz Stephen D. Miller Kingston H.G. Mills Hans Minderman Jenny Mjösberg Jonni Moore Barry Moran Lorenzo Moretta Tim R. Mosmann Susann Müller Gabriele Multhoff Luis Enrique Muñoz Christian Münz Toshinori Nakayama Milena Nasi Katrin Neumann Lai Guan Ng Antonia Niedobitek Sussan Nourshargh Gabriel Núñez José‐Enrique O'Connor Aaron Ochel Anna Oja Diana Ordonez Alberto Orfao Eva Orlowski‐Oliver Wenjun Ouyang Annette Oxenius Raghavendra Palankar Isabel Panse Kovit Pattanapanyasat Malte Paulsen Dinko Pavlinic Livius Penter Pärt Peterson Christian Peth Jordi Petriz Federica Piancone Winfried F. Pickl Silvia Piconese Marcello Pinti A. Graham Pockley Malgorzata Justyna Podolska Zhiyong Poon Katharina Pracht Immo Prinz Carlo E. M. Pucillo Sally A. Quataert Linda Quatrini Kylie M. Quinn Helena Radbruch Tim R. D. J. Radstake Susann Rahmig Hans‐Peter Rahn Bartek Rajwa Gevitha Ravichandran Yotam Raz Jonathan A. Rebhahn Diether Recktenwald Dorothea Reimer Caetano Reis e Sousa Ester B.M. Remmerswaal Lisa Richter Laura G. Rico Andy Riddell Aja M. Rieger J. Paul Robinson Chiara Romagnani Anna Rubartelli Jürgen Ruland Armin Saalmüller Yvan Saeys Takashi Saito Shimon Sakaguchi Francisco Sala‐de‐Oyanguren Yvonne Samstag Sharon Sanderson Inga Sandrock Angela Santoni Ramon Bellmàs Sanz Marina Saresella Catherine Sautes‐Fridman Birgit Sawitzki Linda Schadt Alexander Scheffold Hans U. Scherer Matthias Schiemann Frank A. Schildberg Esther Schimisky Andreas Schlitzer Josephine Schlosser Stephan Schmid Steffen Schmitt Kilian Schober Daniel Schraivogel Wolfgang Schuh Thomas Schüler Reiner Schulte Axel Ronald Schulz Sebastian R. Schulz Cristiano Scottá Daniel Scott‐Algara David P. Sester T. Vincent Shankey Bruno Silva‐Santos Anna Katharina Simon Katarzyna M. Sitnik Silvano Sozzani Daniel E. Speiser Josef Spidlen Anders Stahlberg Alan M. Stall Natalie Stanley Regina Stark Christina Stehle Tobit Steinmetz Hannes Stockinger Yousuke Takahama Kiyoshi Takeda Leonard Tan Attila Tárnok Gisa Tiegs Gergely Toldi Julia Tornack Elisabetta Traggiai Mohamed Trebak Timothy I.M. Tree Joe Trotter John Trowsdale Maria Tsoumakidou Henning Ulrich Sophia Urbanczyk Willem van de Veen Maries van den Broek Edwin van der Pol Sofie Van Gassen Gert Van Isterdael René A.W. van Lier Marc Veldhoen Salvador Vento‐Asturias Paulo Vieira David Voehringer Hans‐Dieter Volk Anouk von Borstel Konrad von Volkmann Ari Waisman Rachael V. Walker Paul K. Wallace Sa A. Wang Xin M. Wang Michael D. Ward Kirsten A Ward‐Hartstonge Klaus Warnatz Gary Warnes Sarah Warth Claudia Waskow James V. Watson Carsten Watzl Leonie Wegener Thomas Weisenburger Annika Wiedemann Jürgen Wienands Anneke Wilharm Robert John Wilkinson Gerald Willimsky James B. Wing Rieke Winkelmann Thomas H. Winkler Oliver F. Wirz Alicia Wong Peter Wurst Jennie H. M. Yang Juhao Yang Maria Yazdanbakhsh Liping Yu Alice Yue Hanlin Zhang Yi Zhao Susanne Maria Ziegler Christina Zielinski Jakob Zimmermann Arturo Zychlinsky., These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion., This work was supported by the Netherlands Organisation for Scientific Research – Domain Applied and Engineering Sciences (NWO-TTW), research program VENI 15924. This work was funded by the Deutsche Forschungsgemeinschaft. European Union Innovative Medicines Initiative - Joint Undertaking - RTCure Grant Agreement 777357 and innovation program (Grant Agreement 695551).

Published
2019

46. Pathogenicity of In Vivo Generated Intestinal Th17 Lymphocytes is IFNγ Dependent

Author

Giulia Lovati, Maria Rescigno, Fulvia Milena Cribiù, Jens Geginat, Antonino Neri, Giulia Nizzoli, Katia Todoerti, Laura Porretti, Elena Trombetta, Claudia Burrello, Flavio Caprioli, Maurizio Vecchi, Fiorenzo Botti, Maria Rita Giuffrè, Federica Facciotti, Giulia Ercoli, Moira Paroni, Nizzoli, G, Burrello, C, Cribiu, F, Lovati, G, Ercoli, G, Botti, F, Trombetta, E, Porretti, L, Todoerti, K, Neri, A, Giuffre, M, Geginat, J, Vecchi, M, Rescigno, M, Paroni, M, Caprioli, F, and Facciotti, F

Subjects
Adult, Male, Crohn’s disease, 0301 basic medicine, medicine.medical_treatment, T cell, Permeability, Tight Junctions, Interferon-gamma, Mice, 03 medical and health sciences, 0302 clinical medicine, Crohn Disease, medicine, Animals, Humans, Secretion, Intestinal Mucosa, Aged, Homeodomain Proteins, Mice, Knockout, Lamina propria, Intestinal permeability, Tight junction, intestinal permeability, business.industry, Interleukin-17, Gastroenterology, General Medicine, Middle Aged, Th1 Cells, Colitis, medicine.disease, Intestinal epithelium, Clone Cells, 030104 developmental biology, Cytokine, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, pathogenic determinant, Th17 Cells, Female, Th17, Interleukin 17, business, IFNγ
Abstract

Background and Aims: T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells. Methods: In vivo-generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/-recipients to test their pathogenicity. Human IL-17, IFN gamma/IL-17, and IFN gamma actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated. Results: IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFN gamma secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFN gamma(-/-) mice. Moreover, IFN gamma production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFN gamma secretion by CD-derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins. Conclusions: Intestinal Th17 cell pathogenicity is associated with IFN gamma production, which directly affects intestinal permeability through the disruption of epithelial tight junctions.

Published
2018

47. Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells

Author

Massimiliano Pagani, Silvano Bosari, Maria Lucia Sarnicola, Giancarlo Cesana, Luca Gianotti, Valentina Vaira, Valeria Ranzani, Claudia Politano, Paola Gruarin, Sergio Abrignani, Monica Moro, Elena Provasi, Alberto Arrigoni, Mariacristina Crosti, Andrea Pisani Ceretti, Luigi Santambrogio, Marco De Simone, Jens Geginat, Ilaria Panzeri, M. Totis, Alessandro Palleschi, Nirvana Maroni, Raoul J. P. Bonnal, Giorgio Bovo, Nicola Zucchini, Roberto A. Perego, Enrico Opocher, Saveria Mazzara, Raffaele De Francesco, Grazisa Rossetti, Hendrik G. Stunnenberg, De Simone, M, Arrigoni, A, Rossetti, G, Gruarin, P, Ranzani, V, Politano, C, Bonnal, R, Provasi, E, Sarnicola, M, Panzeri, I, Moro, M, Crosti, M, Mazzara, S, Vaira, V, Bosari, S, Palleschi, A, Santambrogio, L, Bovo, G, Zucchini, N, Totis, M, Gianotti, L, Cesana, G, Perego, R, Maroni, N, Pisani Ceretti, A, Opocher, E, De Francesco, R, Geginat, J, Stunnenberg, H, Abrignani, S, and Pagani, M

Subjects
Resource, 0301 basic medicine, Chemokine, medicine.medical_treatment, Cell, Immunology, chemical and pharmacologic phenomena, CCR8, T-Lymphocytes, Regulatory, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Antigen, Neoplasms, medicine, Humans, Immunology and Allergy, T Regulatory Cells, Human Lymphocytes, Lung tumor, Colorectal tumor, Molecular Biology, biology, Effector, MED/04 - PATOLOGIA GENERALE, Forkhead Transcription Factors, Immunotherapy, Gene expression profiling, 030104 developmental biology, medicine.anatomical_structure, Infectious Diseases, 030220 oncology & carcinogenesis, biology.protein, Cancer research
Abstract

Summary Tumor-infiltrating regulatory T lymphocytes (Treg) can suppress effector T cells specific for tumor antigens. Deeper molecular definitions of tumor-infiltrating-lymphocytes could thus offer therapeutic opportunities. Transcriptomes of T helper 1 (Th1), Th17, and Treg cells infiltrating colorectal or non-small-cell lung cancers were compared to transcriptomes of the same subsets from normal tissues and validated at the single-cell level. We found that tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints, and expressed on the cell surfaces specific signature molecules such as interleukin-1 receptor 2 (IL1R2), programmed death (PD)-1 Ligand1, PD-1 Ligand2, and CCR8 chemokine, which were not previously described on Treg cells. Remarkably, high expression in whole-tumor samples of Treg cell signature genes, such as LAYN, MAGEH1, or CCR8, correlated with poor prognosis. Our findings provide insights into the molecular identity and functions of human tumor-infiltrating Treg cells and define potential targets for tumor immunotherapy., Highlights • Transcriptome analysis performed on tumor-resident CD4+ Th1, Th17, and Treg cells • Tumor-infiltrating Treg cells are defined by the expression of signature genes • Treg-specific signature genes correlate with patients’ survival in both CRC and NSCLC, Tumor-infiltrating regulatory T cells can suppress effector T cells specific for tumor antigens. De Simone et al. (2016) demonstrate that tumor-infiltrating Treg cells display specific gene signatures that were also validated at the single-cell level. These data can contribute to dissect the molecular networks underlying the biology of tumor-infiltrating Treg cells. As part of the IHEC consortium, this study integrates genetic, epigenetic, and transcriptomic profiling in three immune cell types from nearly 200 people to characterize the distinct and cooperative contributions of diverse genomic inputs to transcriptional variation. Explore the Cell Press IHEC webportal at www.cell.com/consortium/IHEC.

Published
2016

48. Intestinal IFN-gamma-producing type 1 regulatory T cells coexpress CCR5 and programmed cell death protein 1 and downregulate IL-10 in the inflamed guts of patients with inflammatory bowel disease

Author

Moira Paroni, Maria Cristina Crosti, Paola Larghi, Chiara Vasco, Paola Gruarin, Sergio Abrignani, Federica Facciotti, Johanna Sophie Alfen, Cristina Frusteri, Nicola Gagliani, Valeria Ranzani, Andrea Iseppon, Flavio Caprioli, Monica Moro, Stefano Gatti, Roberto Bosotti, Jens Geginat, Richard A. Flavell, Stefano Maglie, Massimiliano Pagani, Alfen, J, Larghi, P, Facciotti, F, Gagliani, N, Bosotti, R, Paroni, M, Maglie, S, Gruarin, P, Vasco, C, Ranzani, V, Frusteri, C, Iseppon, A, Moro, M, Crosti, M, Gatti, S, Pagani, M, Caprioli, F, Abrignani, S, Flavell, R, and Geginat, J

Subjects
Adult, Male, 0301 basic medicine, LAG3, Receptors, CCR5, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Immunology, Mice, Transgenic, Biology, T-Lymphocytes, Regulatory, Inflammatory bowel disease, Proinflammatory cytokine, Young Adult, 03 medical and health sciences, Inflammatory bowel disease, regulatory T cells, IL-10, IL-23, medicine, Animals, Humans, Immunology and Allergy, IL-2 receptor, Intestinal Mucosa, Cells, Cultured, Aged, FOXP3, Dendritic cell, Middle Aged, Inflammatory Bowel Diseases, medicine.disease, Mice, Inbred C57BL, Interleukin 10, 030104 developmental biology, Cytokine, Colonic Neoplasms, Cytokines, Female
Abstract

Background: IL-10 is an anti-inflammatory cytokine required for intestinal immune homeostasis. It mediates suppression of T-cell responses by type 1 regulatory T (T(R)1) cells but is also produced by CD25(+) regulatory T (Treg) cells. Objective: We aimed to identify and characterize human intestinal T(R)1 cells and to investigate whether they are a relevant cellular source of IL-10 in patients with inflammatory bowel diseases (IBDs). Methods: CD4(+) T cells isolated from the intestinal lamina propria of human subjects and mice were analyzed for phenotype, cytokine production, and suppressive capacities. Intracellular IL-10 expression by CD4(+) T-cell subsets in the inflamed guts of patients with IBD (Crohn disease or ulcerative colitis) was compared with that in cells from noninflamed control subjects. Finally, the effects of proinflammatory cytokines on T-cell IL-10 expression were analyzed, and IL-1 beta and IL-23 responsiveness was assessed. Results: Intestinal T(R)1 cells could be identified by coexpression of CCR5 and programmed cell death protein 1 (PD-1) in human subjects and mice. CCR5(+) PD-1(+) T(R)1 cells expressed IFN-gamma and efficiently suppressed T-cell proliferation and transfer colitis. Intestinal IFN-gamma(+) T(R)1 cells, but not IL-7 receptor-positive T-H cells or CD25(+) Treg cells, showed lower IL-10 expression in patients with IBDs. T(R)1 cells were responsive to IL-23, and IFN-gamma(+) T(R)1 cells downregulated IL-10 with IL-1 beta and IL-23. Conversely, CD25(+) Treg cells expressed higher levels of IL-1 receptor but showed stable IL-10 expression. Conclusions: We provide the first ex vivo characterization of human intestinal T(R)1 cells. Selective downregulation of IL-10 by IFN-gamma(+) T(R)1 cells in response to proinflammatory cytokines is likely to drive excessive intestinal inflammation in patients with IBDs.

Published
2018

49. Differences in serum and synovial CD4+ T cells and cytokine profiles to stratify patients with inflammatory osteoarthritis and rheumatoid arthritis

Author

Penatti, Alessandra, Facciotti, Federica, De Matteis, Roberta, Larghi, Paola, Paroni, Moira, Murgo, Antonella, De Lucia, Orazio, Pagani, Massimiliano, Pierannunzii, Luca, Truzzi, Marcello, Ioan-Facsinay, Andreea, Abrignani, Sergio, Geginat, Jens, Meroni, Pier Luigi, Penatti, A, Facciotti, F, De Matteis, R, Larghi, P, Paroni, M, Murgo, A, De Lucia, O, Pagani, M, Pierannunzii, L, Truzzi, M, Ioan-Facsinay, A, Abrignani, S, Geginat, J, and Meroni, P

Subjects
Adult, CD4-Positive T-Lymphocytes, Male, lcsh:Diseases of the musculoskeletal system, Synovial Membrane, T helper subsets, Middle Aged, Inflammatory osteoarthritis, Arthritis, Rheumatoid, T-Lymphocyte Subsets, Osteoarthritis, Synovial Fluid, Humans, Cytokines, Rheumatoid arthritis, Inflammatory osteoarthritis, T helper subsets, Cytokines, Blys, Female, Rheumatoid arthritis, lcsh:RC925-935, Blys, Biomarkers, Research Article, Aged
Abstract

Background The aim was to investigate CD4+T-cell subsets, immune cells and their cytokine profiles in blood and synovial compartments in rheumatoid arthritis (RA) and inflammatory osteoarthritis (OA) to define specific immune signatures. Methods Peripheral blood, synovial fluid (SF) and synovial membranes (SM) of RA and OA patients were analyzed. CD4+T-cell subset frequencies were determined by flow cytometry, and cytokine concentrations in serum and SF were measured by ELISA. Results In peripheral blood, OA patients had altered frequencies of regulatory T-cell subsets, and higher frequencies of Th17 and of Th1/17 cells than RA patients. In the synovial compartment of OA patients, conventional Th17 cells were largely excluded, while Th1/17 cells were enriched and more frequent than in RA patients. Conversely, in the synovial compartment of RA patients, regulatory T cells and Tfh cells were enriched and more frequent then in OA patients. IL-17 and Blys were increased both in serum and SF of RA patients, and correlated with autoantibodies and disease activity. Notably, Blys levels were already significantly elevated in RA patients with low disease activity score in 28 joints (DAS28) and without autoantibody positivity. Conclusions Although patients with inflammatory OA have immune activation in the synovial compartment, they display different T-cell subset frequencies and cytokine profiles. Soluble mediators such as Blys might help to discriminate mild clinical forms of RA from inflammatory OA particularly at the onset of the disease. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1305-1) contains supplementary material, which is available to authorized users.

Published
2017

50. Human CD1c+ dendritic cells secrete high levels of IL-12 and potently prime cytotoxic T-cell responses

Author

Federica Facciotti, Petra Neddermann, Chiara Romagnani, Sergio Abrignani, Paola Gruarin, Svenja Steinfelder, Raffaele De Francesco, Anja Weick, Giulia Nizzoli, Annalisa Bianco, Lorenzo Pignataro, Carmen Scheibenbogen, Jens Geginat, Monica Moro, K Stölzel, Mariacristina Crosti, Bodo Steckel, Sara Torretta, Jana Krietsch, Nizzoli, G, Krietsch, J, Weick, A, Steinfelder, S, Facciotti, F, Gruarin, P, Bianco, A, Steckel, B, Moro, M, Crosti, M, Romagnani, C, Stölzel, K, Torretta, S, Pignataro, L, Scheibenbogen, C, Neddermann, P, De Francesco, R, Abrignani, S, and Geginat, J

Subjects
CD4-Positive T-Lymphocytes, Immunology, Antigen presentation, Cell Separation, CD8-Positive T-Lymphocytes, Biology, Dendritic Cell, Lymphocyte Activation, Biochemistry, Antigens, CD1, Interferon-gamma, Mice, medicine, Animals, Humans, Cytotoxic T cell, Interferon gamma, Secretion, Cytotoxicity, Cytokine, Toll-Like Receptor, Glycoproteins, Cell Proliferation, Antigen Presentation, Animal, Cell growth, Toll-Like Receptors, Interferon-alpha, Dendritic Cells, CD8-Positive T-Lymphocyte, Cell Biology, Hematology, Interleukin-12, Cell biology, Phenotype, CD4-Positive T-Lymphocyte, Interleukin 12, Cytokines, Glycoprotein, Immunologic Memory, CD8, Human, T-Lymphocytes, Cytotoxic, medicine.drug
Abstract

Dendritic cells (DC) have the unique capacities to induce primary T-cell responses. In mice, CD8α(+)DC are specialized to cross-prime CD8(+) T cells and produce interleukin-12 (IL-12) that promotes cytotoxicity. Human BDCA-3(+)DC share several relevant characteristics with CD8α(+)DC, but the capacities of human DC subsets to induce CD8(+) T-cell responses are incompletely understood. Here we compared CD1c(+) myeloid DC (mDC)1, BDCA-3(+)mDC2, and plasmacytoid DC (pDC) in peripheral blood and lymphoid tissues for phenotype, cytokine production, and their capacities to prime cytotoxic T cells. mDC1 were surprisingly the only human DC that secreted high amounts of IL-12p70, but they required combinational Toll-like receptor (TLR) stimulation. mDC2 and pDC produced interferon-λ and interferon-α, respectively. Importantly, mDC1 and mDC2 required different combinations of TLR ligands to cross-present protein antigens to CD8(+) T cells. pDC were inefficient and also expressed lower levels of major histocompatibility complex and co-stimulatory molecules. Nevertheless, all DC induced CD8(+) memory T-cell expansions upon licensing by CD4(+) T cells, and primed naive CD8(+) T cells following appropriate TLR stimulation. However, because mDC1 produced IL-12, they induced the highest levels of cytotoxic molecules. In conclusion, CD1c(+)mDC1 are the relevant source of IL-12 for naive T cells and are fully equipped to cross-prime cytotoxic T-cell responses.

Published
2013

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