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52. Th17-to-Tfh plasticity during periodontitis limits disease pathology

Author

McClure, Flora A., Wemyss, Kelly, Cox, Joshua R., Bridgeman, Hayley M., Prise, Ian E., King, James I., Jaigirdar, Shafqat, Whelan, Annie, Jones, Gareth W., Grainger, John R., Hepworth, Matthew R., and Konkel, Joanne E.

Abstract

Th17 cell plasticity is crucial for development of autoinflammatory disease pathology. Periodontitis is a prevalent inflammatory disease where Th17 cells mediate key pathological roles, yet whether they exhibit any functional plasticity remains unexplored. We found that during periodontitis, gingival IL-17 fate-mapped T cells still predominantly produce IL-17A, with little diversification of cytokine production. However, plasticity of IL-17 fate-mapped cells did occur during periodontitis, but in the gingiva draining lymph node. Here, some Th17 cells acquired features of Tfh cells, a functional plasticity that was dependent on IL-6. Notably, Th17-to-Tfh diversification was important to limit periodontitis pathology. Preventing Th17-to-Tfh plasticity resulted in elevated periodontal bone loss that was not simply due to increased proportions of conventional Th17 cells. Instead, loss of Th17-to-Tfh cells resulted in reduced IgG levels within the oral cavity and a failure to restrict the biomass of the oral commensal community. Thus, our data identify a novel protective function for a subset of otherwise pathogenic Th17 cells during periodontitis.

Published
2024
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53. Impaired Interleukin‐27–Mediated Control of CD4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome.

Author

Lucchesi, Davide, Coleby, Rachel, Pontarini, Elena, Prediletto, Edoardo, Rivellese, Felice, Hill, David G., Derrac Soria, Alicia, Jones, Simon A., Humphreys, Ian R., Sutcliffe, Nurhan, Tappuni, Anwar R., Pitzalis, Costantino, Jones, Gareth W., and Bombardieri, Michele

Subjects
CYTOKINES, DENDRITIC cells, ENZYME-linked immunosorbent assay, FLUORESCENT antibody technique, GENE expression, INTERLEUKINS, LYMPHOID tissue, MICE, MICROSCOPY, SJOGREN'S syndrome, T cells, DESCRIPTIVE statistics, IN vitro studies, SIALADENITIS
Abstract

Objective: Ectopic lymphoid structures (ELS) develop at sites of infection, autoimmunity, and cancer. In patients with Sjögren's syndrome (SS), ELS support autoreactive B cell activation and lymphomagenesis. Interleukin‐27 (IL‐27) is a key regulator of adaptive immunity and limits Th17 cell–driven pathology. We undertook this study to elucidate the role of IL‐27 in ELS formation and function in autoimmunity using a murine model of sialadenitis and in patients with SS. Methods: ELS formation was induced in wild‐type and Il27ra−/− mice via salivary gland (SG) cannulation of a replication‐deficient adenovirus in the presence or absence of IL‐17A neutralization. In SG biopsy samples, IL‐27–producing cells were identified by multicolor immunofluorescence microscopy. Lesional and circulating IL‐27 levels were determined by gene expression and enzyme‐linked immunosorbent assay. The in vitro effect of IL‐27 on T cells was assessed using fluorescence‐activated cell sorting and cytokine release. Results: In experimental sialadenitis, Il27ra−/− mice had larger and more hyperactive ELS (focus score; P < 0.001), increased autoimmunity, and an expanded Th17 response (P < 0.001), compared to wild‐type mice. IL‐17 blockade in Il27ra−/− mice suppressed the aberrant ELS response (B and T cell reduction against control; P < 0.01). SS patients displayed increased circulating IL‐27 levels (P < 0.01), and in SG biopsy samples, IL‐27 was expressed by DC‐LAMP+ dendritic cells in association with CD3+ T cells. Remarkably, in SS T cells (but not in T cells from patients with rheumatoid arthritis or healthy controls), IL‐27–mediated suppression of IL‐17 secretion was severely impaired and associated with an aberrant interferon‐γ release upon IL‐27 stimulation. Conclusion: Our data indicate that the physiologic ability of IL‐27 to limit the magnitude and function of ELS through control of Th17 cell expansion is severely impaired in SS patients, highlighting a defective immunoregulatory checkpoint in this condition. [ABSTRACT FROM AUTHOR]

Published
2020
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54. TH17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity.

Author

Harbour, Stacey N., DiToro, Daniel F., Witte, Steven J., Zindl, Carlene L., Gao, Min, Schoeb, Trenton R., Jones, Gareth W., Jones, Simon A., Hatton, Robin D., and Weaver, Casey T.

Abstract

TH17 sustenance via IL-6: The pathogenic role of the TH17 subset of CD4+ T cells in multiple immune-mediated diseases has prompted close scrutiny of the cytokine signals that promote differentiation and maintenance of TH17 cells. IL-6 and TGF-β are key cytokines for TH17 commitment by naïve T cells whereas IL-23 supports maintenance of a TH17 identity. Harbour et al. investigated whether persistent IL-6 signaling is also needed to sustain TH17 cell functions. IL-6Rα–deficient mouse T cells could not maintain a TH17 phenotype and were attenuated in their ability to elicit colitis in an in vivo cell transfer model. These studies provide deeper insights into the set of signals required for TH17 cell maintenance and suggest additional molecular targets for pharmacological interventions aimed at antagonizing pathogenic TH17 immunity. Acting in concert with TGF-β, interleukin-6 (IL-6) signaling induces T helper 17 (TH17) cell development by programming TH17-related genes via signal transducers and activators of transcription 3 (STAT3). A role for IL-6 signaling beyond the inductive phase of TH17 cell development has not been defined because IL-23 signaling downstream of TH17 cell induction also activates STAT3 and is thought responsible for TH17 cell maintenance. Here, we find that IL-6 signaling is required for both induction and maintenance of mouse TH17 cells; IL-6Rα–deficient TH17 cells rapidly lost their TH17 phenotype and did not cause disease in two models of colitis. Cotransfer of wild-type TH17 cells with IL-6Rα–deficient TH17 cells induced colitis but was unable to rescue phenotype loss of the latter. High IL-6 expression in the colon promoted classic, or cis, rather than transreceptor signaling that was required for maintenance of TH17 cells. Thus, ongoing classic IL-6 signaling underpins the TH17 program and is required for TH17 cell maintenance and function. [ABSTRACT FROM AUTHOR]

Published
2020
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55. Mast cells in early rheumatoid arthritis associate with disease severity and support B cell autoantibody production

Author

Rivellese, Felice, primary, Mauro, Daniele, additional, Nerviani, Alessandra, additional, Pagani, Sara, additional, Fossati-Jimack, Liliane, additional, Messemaker, Tobias, additional, Kurreeman, Fina A S, additional, Toes, René E M, additional, Ramming, Andreas, additional, Rauber, Simon, additional, Schett, Georg, additional, Jones, Gareth W, additional, Jones, Simon A, additional, Rossi, Francesca Wanda, additional, de Paulis, Amato, additional, Marone, Gianni, additional, El Shikh, Mohey Eldin M, additional, Humby, Frances, additional, and Pitzalis, Costantino, additional

Published
2018
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56. Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence

Author

Clement, Mathew, Marsden, Morgan, Stacey, Maria A., Abdul-Karim, Juneid, Gimeno Brias, Silvia, Costa Bento, Diana, Scurr, Martin J., Ghazal, Peter, Weaver, Casey T., Carlesso, Gianluca, Clare, Simon, Jones, Simon A., Godkin, Andrew, Jones, Gareth W., and Humphreys, Ian R.

Subjects
CD4-Positive T-Lymphocytes, Interleukin-27, Physiology, Cytomegalovirus, Salivary Glands, White Blood Cells, Mice, Animal Cells, Immune Physiology, Medicine and Health Sciences, Biology (General), Mice, Knockout, Innate Immune System, T Cells, Viral Persistence and Latency, Interleukin-10, QR180, Cytomegalovirus Infections, Interferon Type I, Cytokines, Cellular Types, Anatomy, Research Article, QH301-705.5, Immune Cells, Immunology, Cytotoxic T cells, Research and Analysis Methods, Microbiology, Exocrine Glands, Virology, Animals, Humans, Molecular Biology Techniques, Molecular Biology, QR355, Blood Cells, Biology and Life Sciences, Cell Biology, cytomegalovirus, CD4+ T-cells, IL-10, IL-27R, type-I IFN, Molecular Development, RC581-607, Viral Replication, Mice, Inbred C57BL, Disease Models, Animal, Immune System, Immunologic diseases. Allergy, Digestive System, Spleen, Cloning, Developmental Biology
Abstract

CD4+ T cells support host defence against herpesviruses and other viral pathogens. We identified that CD4+ T cells from systemic and mucosal tissues of hosts infected with the β-herpesviridae human cytomegalovirus (HCMV) or murine cytomegalovirus (MCMV) express the regulatory cytokine interleukin (IL)-10. IL-10+CD4+ T cells co-expressed TH1-associated transcription factors and chemokine receptors. Mice lacking T cell-derived IL-10 elicited enhanced antiviral T cell responses and restricted MCMV persistence in salivary glands and secretion in saliva. Thus, IL-10+CD4+ T cells suppress antiviral immune responses against CMV. Expansion of this T-cell population in the periphery was promoted by IL-27 whereas mucosal IL-10+ T cell responses were ICOS-dependent. Infected Il27rα-deficient mice with reduced peripheral IL-10+CD4+ T cell accumulation displayed robust T cell responses and restricted MCMV persistence and shedding. Temporal inhibition experiments revealed that IL-27R signaling during initial infection was required for the suppression of T cell immunity and control of virus shedding during MCMV persistence. IL-27 production was promoted by type-I IFN, suggesting that β-herpesviridae exploit the immune-regulatory properties of this antiviral pathway to establish chronicity. Further, our data reveal that cytokine signaling events during initial infection profoundly influence virus chronicity., Author Summary Viruses including the pathogenic β-herpesvirus human cytomegalovirus (HCMV) can replicate within and disseminate from mucosal tissues. Understanding how to improve antiviral immune responses to restrict virus replication in the mucosa could help counter virus transmission. Studies in the murine cytomegalovirus (MCMV) model have demonstrated the importance of the CD4+ T cells in control of mucosal MCMV replication. However, this process is inefficient, allowing virus persistence. Herein, we reveal that production by CD4+ T cells of the immune-suppressive soluble protein, or cytokine, interleukin (IL)-10 facilitates virus persistence in mucosal tissue. Mice deficient in T cell-derived IL-10 mounted heightened T cell responses and reduced virus replication in the salivary glands and shedding in the saliva. The cytokine IL-27 induced IL-10-producing CD4+ T cells in the periphery whereas a cell surface-expressed protein, ICOS, promoted mucosal IL-10+ T cell responses. IL-27 acted in the initial stages of infection to impinge on T cell responses and antiviral control. In turn, IL-27 production in response to viral infection was triggered by type-I interferon, a prototypic antiviral cytokine. Thus, our data suggest that herpesviruses may exploit immune-suppressive properties of this early antiviral cytokine response to facilitate persistence within and shedding from mucosal tissue.

Published
2016
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57. Understanding immune cells in tertiary lymphoid organ development:it is all starting to come together

Author

Jones, Gareth W., Hill, David G., and Jones, Simon A.

Subjects
rheumatoid arthritis, tertiary lymphoid organs, Immunology, autoimmunity, Immunology and Allergy, cancer, ectopic lymphoid structures, lymphoid neogenesis, infection
Abstract

Tertiary lymphoid organs (TLOs) are frequently observed in tissues affected by non-resolving inflammation as a result of infection, autoimmunity, cancer, and allograft rejection. These highly ordered structures resemble the cellular composition of lymphoid follicles typically associated with the spleen and lymph node compartments. Although TLOs within tissues show varying degrees of organization, they frequently display evidence of segregated T and B cell zones, follicular dendritic cell networks, a supporting stromal reticulum, and high endothelial venules. In this respect, they mimic the activities of germinal centers and contribute to the local control of adaptive immune responses. Studies in various disease settings have described how these structures contribute to either beneficial or deleterious outcomes. While the development and architectural organization of TLOs within inflamed tissues requires homeostatic chemokines, lymphoid and inflammatory cytokines, and adhesion molecules, our understanding of the cells responsible for triggering these events is still evolving. Over the past 10–15 years, novel immune cell subsets have been discovered that have more recently been implicated in the control of TLO development and function. In this review, we will discuss the contribution of these cell types and consider the potential to develop new therapeutic strategies that target TLOs.

Published
2016
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61. IL-27 Induced by Select Candida spp. via TLR7/NOD2 Signaling and IFN-β Production Inhibits Fungal Clearance

Author

Patin, Emmanuel C., primary, Jones, Adam V., additional, Thompson, Aiysha, additional, Clement, Mathew, additional, Liao, Chia-Te, additional, Griffiths, James S., additional, Wallace, Leah E., additional, Bryant, Clare E., additional, Lang, Roland, additional, Rosenstiel, Philip, additional, Humphreys, Ian R., additional, Taylor, Philip R., additional, Jones, Gareth W., additional, and Orr, Selinda J., additional

Published
2016
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62. Activation of naïve CD4+T cells re-tunes STAT1 signaling to deliver unique cytokine responses in memory CD4+T cells

Author

Twohig, Jason P., Cardus Figueras, Ana, Andrews, Robert, Wiede, Florian, Cossins, Benjamin C., Derrac Soria, Alicia, Lewis, Myles J., Townsend, Michael J., Millrine, David, Li, Jasmine, Hill, David G., Uceda Fernandez, Javier, Liu, Xiao, Szomolay, Barbara, Pepper, Christopher J., Taylor, Philip R., Pitzalis, Costantino, Tiganis, Tony, Williams, Nigel M., Jones, Gareth W., and Jones, Simon A.

Abstract

The cytokine IL-6 controls the survival, proliferation and effector characteristics of lymphocytes through activation of the transcription factors STAT1 and STAT3. While STAT3 activity is an ever-present feature of IL-6 signaling in CD4+T cells, prior activation via the T cell antigen receptor limits IL-6’s control of STAT1 in effector and memory populations. Here we found that phosphorylation of STAT1 in response to IL-6 was regulated by the tyrosine phosphatases PTPN2 and PTPN22 expressed in response to the activation of naïve CD4+T cells. Transcriptomics and chromatin immunoprecipitation–sequencing (ChIP-seq) of IL-6 responses in naïve and effector memory CD4+T cells showed how the suppression of STAT1 activation shaped the functional identity and effector characteristics of memory CD4+T cells. Thus, tyrosine phosphatases induced by the activation of naïve T cells determine the way activated or memory CD4+T cells sense and interpret cytokine signals.

Published
2019
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63. Interleukin-6 signaling drives fibrosis in unresolved inflammation

Author

Fielding, Ceri A., Jones, Gareth W., McLoughlin, Rachel M., McLeod, Louise, Hammond, Victoria J., Uceda, Javier, Williams, Anwen S., Lambie, Mark, Foster, Thomas L., Liao, Chia-Te, Rice, Christopher M., Greenhill, Claire J., Colmont, Chantal S., Hams, Emily, Coles, Barbara, Kift-Morgan, Ann, Newton, Zarabeth, Craig, Katherine J., Williams, John D., Williams, Geraint T., Davies, Simon J., Humphreys, Ian R., O’Donnell, Valerie B., Taylor, Philip R., Jenkins, Brendan J., Topley, Nicholas, and Jones, Simon A.

Subjects
Feedback, Physiological, Mice, Knockout, Interleukin-6, Immunology, Peritonitis, Th1 Cells, R1, Adoptive Transfer, Fibrosis, Article, Extracellular Matrix, Mice, Inbred C57BL, Disease Models, Animal, Interferon-gamma, Mice, Infectious Diseases, STAT1 Transcription Factor, Acute Disease, Chronic Disease, Immunology and Allergy, Animals, Humans, Peritoneum, Cells, Cultured, Signal Transduction
Abstract

Summary Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-γ (IFN-γ), STAT1, or RAG-1. Here, IFN-γ and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation., Highlights • Repeated acute resolving inflammation leads to excessive tissue damage • IL-6 regulates profibrotic IFN-γ-secreting T cells • IFN-γ increases detrimental STAT1 signaling in stromal tissue • STAT1 activity alters homeostatic control of extracellular matrix to promote fibrosis

Published
2012

64. Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis

Author

Jones, Gareth W., primary, Bombardieri, Michele, additional, Greenhill, Claire J., additional, McLeod, Louise, additional, Nerviani, Alessandra, additional, Rocher-Ros, Vidalba, additional, Cardus, Anna, additional, Williams, Anwen S., additional, Pitzalis, Costantino, additional, Jenkins, Brendan J., additional, and Jones, Simon A., additional

Published
2015
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65. 128

Author

McLeod, Louise E., primary, Jones, Gareth W., additional, Najdovska, Meri, additional, and Jenkins, Brendan J., additional

Published
2014
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66. 186

Author

Twohig, Jason P., primary, Cardus, Anna, additional, Jones, Gareth W., additional, and Jones, Simon A., additional

Published
2014
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69. Interleukin-10 regulates the inflammasome-driven augmentation of inflammatory arthritis and joint destruction

Author

Greenhill, Claire J, primary, Jones, Gareth W, additional, Nowell, Mari A, additional, Newton, Zarabeth, additional, Harvey, Ann K, additional, Moideen, Abdul N, additional, Collins, Fraser L, additional, Bloom, Anja C, additional, Coll, Rebecca C, additional, Robertson, Avril AB, additional, Cooper, Matthew A, additional, Rosas, Marcela, additional, Taylor, Philip R, additional, O'Neill, Luke A, additional, Humphreys, Ian R, additional, Williams, Anwen S, additional, and Jones, Simon A, additional

Published
2014
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70. 212

Author

Rice, Christopher M., primary, Greenhill, Claire J., additional, Jones, Gareth W., additional, Aldrovandi, Maceler, additional, Hammond, Victoria J., additional, O’Donnell, Valerie B., additional, Topley, Nicholas, additional, Taylor, Philip R., additional, and Jones, Simon A., additional

Published
2013
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71. 79

Author

Fielding, Ceri A., primary, Jones, Gareth W., additional, Taylor, Philip R., additional, Jenkins, Brendan J., additional, Topley, Nicholas, additional, and Jones, Simon A., additional

Published
2013
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72. 134

Author

Jones, Gareth W., primary, Bombardieri, Michele, additional, Greenhill, Claire J., additional, McLeod, Louise, additional, Rocher, Vidalba, additional, Williams, Anwen S., additional, Pitzalis, Costantino, additional, Jenkins, Brendan J., additional, and Jones, Simon A., additional

Published
2013
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73. LAB/NTAL Facilitates Fungal/PAMP-induced IL-12 and IFN-γ Production by Repressing β-Catenin Activation in Dendritic Cells

Author

Orr, Selinda J., primary, Burg, Ashley R., additional, Chan, Tim, additional, Quigley, Laura, additional, Jones, Gareth W., additional, Ford, Jill W., additional, Hodge, Deborah, additional, Razzook, Catherine, additional, Sarhan, Joseph, additional, Jones, Yava L., additional, Whittaker, Gillian C., additional, Boelte, Kimberly C., additional, Lyakh, Lyudmila, additional, Cardone, Marco, additional, O'Connor, Geraldine M., additional, Tan, Cuiyan, additional, Li, Hongchuan, additional, Anderson, Stephen K., additional, Jones, Simon A., additional, Zhang, Weiguo, additional, Taylor, Philip R., additional, Trinchieri, Giorgio, additional, and McVicar, Daniel W., additional

Published
2013
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74. Cytomegalovirus-Specific IL-10-Producing CD4+ T Cells Are Governed by Type-I IFN-Induced IL-27 and Promote Virus Persistence.

Author

Clement, Mathew, Marsden, Morgan, Stacey, Maria A., Abdul-Karim, Juneid, Gimeno Brias, Silvia, Costa Bento, Diana, Scurr, Martin J., Ghazal, Peter, Weaver, Casey T., Carlesso, Gianluca, Clare, Simon, Jones, Simon A., Godkin, Andrew, Jones, Gareth W., and Humphreys, Ian R.

Subjects
CYTOMEGALOVIRUSES, HERPESVIRUS diseases, LABORATORY mice, INTERLEUKINS, CHEMOKINES, TRANSCRIPTION factors
Abstract

CD4+ T cells support host defence against herpesviruses and other viral pathogens. We identified that CD4+ T cells from systemic and mucosal tissues of hosts infected with the β-herpesviridae human cytomegalovirus (HCMV) or murine cytomegalovirus (MCMV) express the regulatory cytokine interleukin (IL)-10. IL-10+CD4+ T cells co-expressed TH1-associated transcription factors and chemokine receptors. Mice lacking T cell-derived IL-10 elicited enhanced antiviral T cell responses and restricted MCMV persistence in salivary glands and secretion in saliva. Thus, IL-10+CD4+ T cells suppress antiviral immune responses against CMV. Expansion of this T-cell population in the periphery was promoted by IL-27 whereas mucosal IL-10+ T cell responses were ICOS-dependent. Infected Il27rα-deficient mice with reduced peripheral IL-10+CD4+ T cell accumulation displayed robust T cell responses and restricted MCMV persistence and shedding. Temporal inhibition experiments revealed that IL-27R signaling during initial infection was required for the suppression of T cell immunity and control of virus shedding during MCMV persistence. IL-27 production was promoted by type-I IFN, suggesting that β-herpesviridae exploit the immune-regulatory properties of this antiviral pathway to establish chronicity. Further, our data reveal that cytokine signaling events during initial infection profoundly influence virus chronicity. [ABSTRACT FROM AUTHOR]

Published
2016
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77. CS11-5. Inhibition of Interleukin 6 classic signaling is a novel function of soluble gp130 which is controlled by the ratio of Interleukin 6 and soluble Interleukin 6 receptor

Author

Garbers, Christoph, primary, Thaiss, Wolfgang, additional, Waetzig, Georg H., additional, Jones, Gareth W., additional, Floss, Doreen M., additional, Lorenzen, Inken, additional, Grötzinger, Joachim, additional, Jones, Simon A., additional, Rose-John, Stefan, additional, and Scheller, Jürgen, additional

Published
2011
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78. Although IL-6 Trans-Signaling Is Sufficient To Drive Local Immune Responses, Classical IL-6 Signaling Is Obligate for the Induction of T Cell-Mediated Autoimmunity

Author

Lissilaa, Rami, primary, Buatois, Vanessa, additional, Magistrelli, Giovanni, additional, Williams, Anwen S., additional, Jones, Gareth W., additional, Herren, Suzanne, additional, Shang, Limin, additional, Malinge, Pauline, additional, Guilhot, Florence, additional, Chatel, Laurence, additional, Hatterer, Eric, additional, Jones, Simon A., additional, Kosco-Vilbois, Marie H., additional, and Ferlin, Walter G., additional

Published
2010
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80. Naive and activated T cells display differential responsiveness to TL1A that affects Th17 generation, maintenance, and proliferation

Author

Jones, Gareth W., primary, Stumhofer, Jason S., additional, Foster, Tom, additional, Twohig, Jason P., additional, Hertzog, Paul, additional, Topley, Nicholas, additional, Williams, Anwen S., additional, Hunter, Christopher A., additional, Jenkins, Brendan J., additional, Wang, Eddie C. Y., additional, and Jones, Simon A., additional

Published
2010
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81. Loss of CD4+ T Cell IL-6R Expression during Inflammation Underlines a Role for IL-6 Trans Signaling in the Local Maintenance of Th17 Cells

Author

Jones, Gareth W., primary, McLoughlin, Rachel M., additional, Hammond, Victoria J., additional, Parker, Clare R., additional, Williams, John D., additional, Malhotra, Raj, additional, Scheller, Jürgen, additional, Williams, Anwen S., additional, Rose-John, Stefan, additional, Topley, Nicholas, additional, and Jones, Simon A., additional

Published
2010
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82. Therapeutic Targeting of IL-6 Trans Signaling Counteracts STAT3 Control of Experimental Inflammatory Arthritis

Author

Nowell, Mari A., primary, Williams, Anwen S., additional, Carty, Sarah A., additional, Scheller, Jürgen, additional, Hayes, Anthony J., additional, Jones, Gareth W., additional, Richards, Peter J., additional, Slinn, Simon, additional, Ernst, Matthias, additional, Jenkins, Brendan J., additional, Topley, Nicholas, additional, Rose-John, Stefan, additional, and Jones, Simon A., additional

Published
2009
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99. Naive and activated T cells display differential responsiveness to TL1A that affects Th17 generation, maintenance, and proliferation.

Author

Jones, Gareth W., Stumhofer, Jason S., Foster, Tom, Twohig, Jason P., Hertzog, Paul, Topley, Nicholas, Williams, Anwen S., Hunter, Christopher A., Jenkins, Brendan J., Wang, Eddie C. Y., and Jones, Simon A.

Subjects
*TUMOR necrosis factors, *T cells, *DEATH receptors, *FLOW cytometry, *INTERLEUKIN-2, *CELLS
Abstract

Tumor necrosis factor (TNF)-like cyto-kine (TL1A) is a T-cell costimulator that bolsters cyto- kine-induced activation through death receptor 3 (DR3). To explore the relationship between T-cell activation and TL1A responsiveness, flow cytometry profiled DR3 expression in resting and activated T cells. In human CD4+ T cells, DR3 was induced rapidly following activation and expressed prominently by in-terleukin (IL)-17-secreting T cells (Thl7). Splenic T cells from wild-type and DR3-deficient mice showed that TL1A activation of DR3 inhibits Thl7 generation (81 ± 2.6% at 100 ng/ml TL1A) from naive T cells. This response was not associated with suppression of T-cell proliferation. Using neutralizing antibodies or T cells derived from genetically modified mice, TL1A inhibition of Th17 development was found to be independent of IL-2, IL-27, γFN, IFNAR1, and STAT1. 17A secretion, however, the reduced threshold of Under suboptimal TCR activation, TL1A continued to block IL-17A secretion, however, the reduced threshold of TCR engagement was now linked with an increase in TL1A-driven proliferation. In contrast, fully committed Thl7 cells displayed an altered TL1A responsiveness and in the absence of TCR costimulation supported the maintenance of T cell IL-17A expression. Consequently, TL1A orchestrates unique outcomes in naive and effector T-helper cells, which may affect the proliferation, differentiation and maintenance of Thl7 cells in peripheral compartments and inflamed tissues. [ABSTRACT FROM AUTHOR]

Published
2011
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