126 results on '"Löhning M"'
Search Results
2. LOCAL AND SYSTEMIC IMMUNE RESPONSE IN A POST-TRAUMATIC OSTEOARTHRITIS MODEL.
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Hernández, N. A. Durán, primary, Rapp, A.E., additional, Panse, I., additional, Liu, X., additional, Dai, Y., additional, Plajer, V., additional, Madrigal-Avilés, A., additional, and Löhning, M., additional
- Published
- 2022
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3. A1.28 Synovial fibroblasts suppress TH1, but not TH2 or TH17 cells, through tryptophan metabolism
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Tykocinski, LO, Lauffer, AM, Bohnen, A, Krienke, S, Tretter, T, Adam, I, Mohapatra, SR, Saikali, P, Löhning, M, Neidhart, M, Gay, S, Oezen, I, Platten, M, Opitz, CA, and Lorenz, HM
- Published
- 2015
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4. Cytokine expression level is a stable feature of differentiated T helper cells: W25.006
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Helmstetter, C., Flodorf, M., Peine, M., Hegazy, A. N., Radbruch, A., Höfer, T., and Löhning, M.
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- 2012
5. TLR1/2 signaling impairs mitochondrial oxidative phosphorylation in human chondrocytes via the induction of nitric oxide
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Shen, P., primary, Nguyen, M., additional, Fuchs, M., additional, Reisener, M.-J., additional, Maleitzke, T., additional, Gwinner, C., additional, Wu, P., additional, Grunwald, L., additional, Jung, T., additional, Winkler, T., additional, Pumberger, M., additional, Perka, C., additional, and Löhning, M., additional
- Published
- 2020
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6. Murine CLCA4A and CLCA4B are Expressed in Partially Different Cellular Niches of the Intestinal Epithelium
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Teske, K., primary, Erickson, N.A., additional, Mundhenk, L., additional, Glauben, R., additional, Dzamukova, M., additional, Löhning, M., additional, and Gruber, A.D., additional
- Published
- 2020
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7. IL-33 in T Cell Differentiation, Function, and Immune Homeostasis
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Peine M Marek RM Löhning M.
- Abstract
Recent studies have highlighted a role for the alarmin interleukin (IL) 33 in CD4+ and CD8+ T cell activation and function and have also revealed important distinctions. The IL 33 receptor ST2 is constitutively and abundantly expressed on T helper 2 (Th2) and GATA 3+ regulatory T cells in a GATA 3 and STAT5 dependent manner. Upon activation Th1 and cytotoxic T cells express ST2 transiently driven by T bet and/or STAT4. We review these findings here and critically examine evidence indicating that IL 33 enhances the differentiation and functionality of various T cell subsets through positive feedback loops involving lineage specifying transcription factors. In this context we discuss how quantitative and qualitative differences in ST2 expression between effector and GATA 3+ regulatory T cells may contribute to immune homeostasis and outline important areas of future inquiry.
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- 2016
8. Toll-like receptor signaling in chondrocyte promotes the development of osteoarthritis
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Shen, P., primary, Fuchs, M., additional, Reisener, M.-J., additional, Grinner, C., additional, Wu, P., additional, Jung, T., additional, Pumberger, M., additional, Parka, C., additional, and Löhning, M., additional
- Published
- 2019
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9. T1/ST2 is preferentially expressed on murine Th2 cells and important for Th2 effector function
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Löhning, M., Grogan, J., Coyle, A. J., Stroehmann, A., Yazdanbakhsh, M., Ramos, J.-C. Gutierrez, Radbruch, A., and Kamradt, Thomas
- Published
- 1998
10. TH17 cells express ST2 and are controlled by the alarmin IL-33 in the small intestine
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Pascual-Reguant, A., primary, Bayat Sarmadi, J., additional, Baumann, C., additional, Noster, R., additional, Cirera-Salinas, D., additional, Curato, C., additional, Pelczar, P., additional, Huber, S., additional, Zielinski, C.E., additional, Löhning, M., additional, Hauser, A.E., additional, and Esplugues, E., additional
- Published
- 2017
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11. T-bet expression by Th cells promotes type 1 inflammation but is dispensable for colitis
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Zimmermann, J., primary, Kühl, A.A., additional, Weber, M., additional, Grün, J.R., additional, Löffler, J., additional, Haftmann, C., additional, Riedel, R., additional, Maschmeyer, P., additional, Lehmann, K., additional, Westendorf, K., additional, Mashreghi, M-F, additional, Löhning, M., additional, Mack, M., additional, Radbruch, A., additional, and Chang, H.D., additional
- Published
- 2016
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12. TH17 cells express ST2 and are controlled by the alarmin IL-33 in the small intestine.
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Pascual-Reguant, A, Bayat Sarmadi, J, Baumann, C, Noster, R, Cirera-Salinas, D, Curato, C, Pelczar, P, Huber, S, Zielinski, C E, Löhning, M, Hauser, A E, and Esplugues, E
- Published
- 2017
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13. IL-33 Receptor-Expressing Regulatory T Cells Are Highly Activated, Th2 Biased and Suppress CD4 T Cell Proliferation through IL-10 and TGFß Release
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Siede J Fröhlich A Datsi A Hegazy AN Varga DV Holecska V Saito H Nakae S Löhning M.
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hemic and immune systems ,chemical and pharmacologic phenomena - Abstract
Immunomodulatory Foxp3+ regulatory T cells (Tregs) form a heterogeneous population consisting of subsets with different activation states migratory properties and suppressive functions. Recently expression of the IL 33 receptor ST2 was shown on Tregs in inflammatory settings. Here we report that ST2 expression identifies highly activated Tregs in mice even under homeostatic conditions. ST2+ Tregs preferentially accumulate at non lymphoid sites likely mediated by their high expression of several chemokine receptors facilitating tissue homing. ST2+ Tregs exhibit a Th2 biased character expressing GATA 3 and producing the Th2 cytokines IL 5 and IL 13 –especially in response to IL 33. Yet IL 33 is dispensable for the generation and maintenance of these cells in vivo. Furthermore ST2+ Tregs are superior to ST2- Tregs in suppressing CD4+ T cell proliferation in vitro independent of IL 33. This higher suppressive capacity is partially mediated by enhanced production and activation of the anti inflammatory cytokines IL 10 and TGFß. Thus ST2 expression identifies a highly activated strongly suppressive Treg subset preferentially located in non lymphoid tissues. Here ST2+ Tregs may be well positioned to immediately react to IL 33 alarm signals. Their specific properties may render ST2+ Tregs useful targets for immunomodulatory therapies.
- Published
- 2016
14. A GATA-3 binding site in the first intron of the interleukin-4 gene defines a critical element for the memory expression of interleukin-4 in Th lymphocytes
- Author
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Tykocinski L, Petra Hajkova, Stamm T, Sözeri O, Löhning M, Friedrich B, Hu-Li J, Pannetier C, Paul W, Grütz G, Walter J, and Radbruch A
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Meeting Abstract - Published
- 2003
15. Sequential production of IL-2, IFN-γ and IL-10 by individual Th lymphocytes
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Löhning, M, primary
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- 1997
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16. Commitment of cytokine expression in individual TH1-like lymphocytes
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Assenmacher, M., primary, Löhning, M., additional, Scheffold, A., additional, Richter, A., additional, Miltenyi, S., additional, Schmitz, J., additional, and Radbruch, A., additional
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- 1997
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17. Survival of long-lived plasma cells is independent of antigen.
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Manz, RA, Löhning, M, Cassese, G, Thiel, A, and Radbruch, A
- Abstract
Recent studies have shown that persistent specific antibody titer is provided by long-lived plasma cells (PC) which constitute a new kind of 'memory-providing cells'. In the present study, we examine the role of antigen for the long-term survival of PC and the maintenance of specific serum antibody titers. Using a novel cytometric technology, to identify and isolate antigen-specific PC, we analyzed long-lived PC of BALB/c mice, during their development (between day 1 and 10) after secondary immunization with ovalbumin (OVA) and in the phase of the established immune reaction. Most if not all OVA-specific PC were generated within a few days after immunization. Within 3 weeks, they matured, as indicated by down-regulation of expression of MHC class II. These PC are long lived and located in spleen and bone marrow. Upon adoptive transfer, OVA-specific PC from bone marrow, but not memory B cells, conferred specific and long-lasting antibody titers to antigen-free IgH syngeneic recipients. In response to antigenic challenge, new OVA-specific antibody-secreting cells were generated from transferred memory B cells. Antibody secretion by long-lived PC was not affected. Our results confirm that persistent antibody titers are provided by long-lived PC, independent of memory B cells and demonstrate that this humoral memory is inert to antigen. [ABSTRACT FROM PUBLISHER]
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- 1998
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18. Aggravation of viral hepatitis by platelet-derived serotonin
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Lang, P A, Contaldo, C, Georgiev, P, El-Badry, A M, Recher, M, Kurrer, M, Cervantes-Barragan, L, Ludewig, B, Calzascia, T, Bolinger, B, Merkler, D, Odermatt, B, Bader, M, Graf, R, Clavien, P A, Hegazy, A N, Löhning, M, Harris, N L, Ohashi, P S, Hengartner, H, Zinkernagel, R M, and Lang, K S
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3. Good health
19. Commitment of individual Th1-like lymphocytes to expression of IFN-gamma versus IL-4 and IL-10: Selective induction of IL-10 by sequential stimulation of naive Th cells with IL-12 and IL-4
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Assenmacher, M., Löhning, M., Alexander Scheffold, Richter, A., Miltenyi, S., Schmitz, J., and Radbruch, A.
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Mice, Inbred BALB C ,Cell Polarity ,Cell Differentiation ,Mice, Transgenic ,Cell Separation ,Th1 Cells ,Flow Cytometry ,Lymphocyte Activation ,Interleukin-12 ,Interleukin-10 ,Interferon-gamma ,Mice ,T-Lymphocyte Subsets ,CD4 Antigens ,Animals ,Interleukin-4 ,L-Selectin - Abstract
Commitment of Th lymphocytes to the Th1 phenotype, as characterized by the expression of the major proinflammatory cytokine IFN-gamma, may be critically involved in the establishment of chronic inflammation and inflammatory autoimmune disease. To date, it has been shown that in IL-12-stimulated murine Th cell lines containing a major fraction of Th1 cells, Th2 cells can be induced by IL-4 until about 2 wk after initial activation, but not later. Here we analyze, based on the magnetic isolation of viable Th1 cells according to their specific expression of IFN-gamma, the cytokine commitment of individual Th1 cells. After activation of naive Th cells with Ag and IL-12 for up to 5 wk, isolated IFN-gamma-producing cells were restimulated with Ag and IL-4. Within the first 3 to 4 wk of IL-12 stimulation, some IFN-gamma+ cells stopped expression of IFN-gamma when restimulated with IL-4. However, within only 1 to 2 wk of IL-12 stimulation, few IFN-gamma+ cells could be converted to produce IL-4. Others continued to express IFN-gamma and thus were already committed to a proinflammatory, Th1-like phenotype. Surprisingly, within 3 wk of IL-12 stimulation, many of the IFN-gamma-producing cells responded to IL-4 restimulation by expression of IL-10, but neither IFN-gamma nor IL-4, i.e., by conversion to a suppressive, anti-inflammatory phenotype.
20. B cells influence on an environmental cue for IL-2-dependent generation of resting memory T helper cells.
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Hojyo, S., Sarkander, J., T. Y. Wu, Mursell, M., Radbruch, A., Löhning, M., and Tokoyoda, K.
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- 2017
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21. MicroRNA-182 promotes clonal expansion of activated T helper cells.
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Stittrich, A-B, Haftmann, C, Hegazy, A, Floessdorf, M, Dong, J, Fuhrmann, F, Heinz, G, Li, N, Fang, Z, Jahn, A, Baumgrass, R, Grün, J, Chen, W, Höfer, T, Löhning, M, Chang, H-D, Rajewsky, N, Radbruch, A, and Mashreghi, M-F
- Published
- 2010
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22. Plasticity and lineage commitment of individual T H 1 cells are determined by stable T-bet expression quantities.
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Hegazy AN, Peine C, Niesen D, Panse I, Vainshtein Y, Kommer C, Zhang Q, Brunner TM, Peine M, Fröhlich A, Ishaque N, Marek RM, Zhu J, Höfer T, and Löhning M
- Subjects
- Animals, Mice, GATA3 Transcription Factor metabolism, GATA3 Transcription Factor genetics, Interferon-gamma metabolism, Gene Expression Regulation, Cytokines metabolism, Th1 Cells immunology, Th1 Cells metabolism, T-Box Domain Proteins metabolism, T-Box Domain Proteins genetics, Cell Lineage genetics, Cell Differentiation, Cell Plasticity, Th2 Cells immunology, Th2 Cells metabolism
- Abstract
T helper 1 (T
H 1) cell identity is defined by the expression of the lineage-specifying transcription factor T-bet. Here, we examine the influence of T-bet expression heterogeneity on subset plasticity by leveraging cell sorting of distinct in vivo-differentiated TH 1 cells based on their quantitative expression of T-bet and interferon-γ. Heterogeneous T-bet expression states were regulated by virus-induced type I interferons and were stably maintained even after secondary viral infection. Exposed to alternative differentiation signals, the sorted subpopulations exhibited graded levels of plasticity, particularly toward the TH 2 lineage: T-bet quantities were inversely correlated with the ability to express the TH 2 lineage-specifying transcription factor GATA-3 and TH 2 cytokines. Reprogramed TH 1 cells acquired graded mixed TH 1 + TH 2 phenotypes with a hybrid epigenetic landscape. Continuous presence of T-bet in differentiated TH 1 cells was essential to ensure TH 1 cell stability. Thus, innate cytokine signals regulate TH 1 cell plasticity via an individual cell-intrinsic rheostat to enable T cell subset adaptation to subsequent challenges.- Published
- 2024
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23. IL-33 controls IL-22-dependent antibacterial defense by modulating the microbiota.
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Röwekamp I, Maschirow L, Rabes A, Fiocca Vernengo F, Hamann L, Heinz GA, Mashreghi MF, Caesar S, Milek M, Fagundes Fonseca AC, Wienhold SM, Nouailles G, Yao L, Mousavi S, Bruder D, Boehme JD, Puzianowska-Kuznicka M, Beule D, Witzenrath M, Löhning M, Klose CSN, Heimesaat MM, Diefenbach A, and Opitz B
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- Animals, Mice, Humans, Mice, Knockout, Microbiota immunology, Mice, Inbred C57BL, Pneumonia, Pneumococcal immunology, Pneumonia, Pneumococcal microbiology, Gastrointestinal Microbiome immunology, Lymphocytes immunology, Lymphocytes metabolism, Polymorphism, Single Nucleotide, Interleukin-33 immunology, Interleukin-33 genetics, Interleukin-33 metabolism, Interleukins metabolism, Interleukins immunology, Interleukins genetics, Interleukin-22, Streptococcus pneumoniae immunology, Immunity, Innate, Interleukin-1 Receptor-Like 1 Protein metabolism, Interleukin-1 Receptor-Like 1 Protein genetics, Interleukin-1 Receptor-Like 1 Protein immunology
- Abstract
IL-22 plays a critical role in defending against mucosal infections, but how IL-22 production is regulated is incompletely understood. Here, we show that mice lacking IL-33 or its receptor ST2 (IL-1RL1) were more resistant to Streptococcus pneumoniae lung infection than wild-type animals and that single-nucleotide polymorphisms in IL33 and IL1RL1 were associated with pneumococcal pneumonia in humans. The effect of IL-33 on S. pneumoniae infection was mediated by negative regulation of IL-22 production in innate lymphoid cells (ILCs) but independent of ILC2s as well as IL-4 and IL-13 signaling. Moreover, IL-33's influence on IL-22-dependent antibacterial defense was dependent on housing conditions of the mice and mediated by IL-33's modulatory effect on the gut microbiota. Collectively, we provide insight into the bidirectional crosstalk between the innate immune system and the microbiota. We conclude that both genetic and environmental factors influence the gut microbiota, thereby impacting the efficacy of antibacterial immune defense and susceptibility to pneumonia., Competing Interests: Competing interests statement:The authors declare no competing interest.
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- 2024
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24. A type 1 immunity-restricted promoter of the IL-33 receptor gene directs antiviral T-cell responses.
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Brunner TM, Serve S, Marx AF, Fadejeva J, Saikali P, Dzamukova M, Durán-Hernández N, Kommer C, Heinrich F, Durek P, Heinz GA, Höfer T, Mashreghi MF, Kühn R, Pinschewer DD, and Löhning M
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- Animals, Humans, Mice, Alarmins, Antiviral Agents, T-Lymphocyte Subsets metabolism, Interleukin-1 Receptor-Like 1 Protein genetics, Interleukin-1 Receptor-Like 1 Protein metabolism, Interleukin-33 genetics
- Abstract
The pleiotropic alarmin interleukin-33 (IL-33) drives type 1, type 2 and regulatory T-cell responses via its receptor ST2. Subset-specific differences in ST2 expression intensity and dynamics suggest that transcriptional regulation is key in orchestrating the context-dependent activity of IL-33-ST2 signaling in T-cell immunity. Here, we identify a previously unrecognized alternative promoter in mice and humans that is located far upstream of the curated ST2-coding gene and drives ST2 expression in type 1 immunity. Mice lacking this promoter exhibit a selective loss of ST2 expression in type 1- but not type 2-biased T cells, resulting in impaired expansion of cytotoxic T cells (CTLs) and T-helper 1 cells upon viral infection. T-cell-intrinsic IL-33 signaling via type 1 promoter-driven ST2 is critical to generate a clonally diverse population of antiviral short-lived effector CTLs. Thus, lineage-specific alternative promoter usage directs alarmin responsiveness in T-cell subsets and offers opportunities for immune cell-specific targeting of the IL-33-ST2 axis in infections and inflammatory diseases., (© 2024. The Author(s).)
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- 2024
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25. NOS inhibition reverses TLR2-induced chondrocyte dysfunction and attenuates age-related osteoarthritis.
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Shen P, Serve S, Wu P, Liu X, Dai Y, Durán-Hernández N, Nguyen DTM, Fuchs M, Maleitzke T, Reisener MJ, Dzamukova M, Nussbaumer K, Brunner TM, Li Y, Holecska V, Heinz GA, Heinrich F, Durek P, Katsoula G, Gwinner C, Jung T, Zeggini E, Winkler T, Mashreghi MF, Pumberger M, Perka C, and Löhning M
- Subjects
- Humans, Mice, Animals, Chondrocytes metabolism, Toll-Like Receptor 2 genetics, Toll-Like Receptor 2 metabolism, Toll-Like Receptors metabolism, Cells, Cultured, Osteoarthritis metabolism, Cartilage, Articular metabolism
- Abstract
Osteoarthritis (OA) is a joint disease featuring cartilage breakdown and chronic pain. Although age and joint trauma are prominently associated with OA occurrence, the trigger and signaling pathways propagating their pathogenic aspects are ill defined. Following long-term catabolic activity and traumatic cartilage breakdown, debris accumulates and can trigger Toll-like receptors (TLRs). Here we show that TLR2 stimulation suppressed the expression of matrix proteins and induced an inflammatory phenotype in human chondrocytes. Further, TLR2 stimulation impaired chondrocyte mitochondrial function, resulting in severely reduced adenosine triphosphate (ATP) production. RNA-sequencing analysis revealed that TLR2 stimulation upregulated nitric oxide synthase 2 ( NOS2 ) expression and downregulated mitochondria function-associated genes. NOS inhibition partially restored the expression of these genes, and rescued mitochondrial function and ATP production. Correspondingly, Nos2
-/- mice were protected from age-related OA development. Taken together, the TLR2-NOS axis promotes human chondrocyte dysfunction and murine OA development, and targeted interventions may provide therapeutic and preventive approaches in OA.- Published
- 2023
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26. The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1 + CD8 + T cells in chronic viral infection.
- Author
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Marx AF, Kallert SM, Brunner TM, Villegas JA, Geier F, Fixemer J, Abreu-Mota T, Reuther P, Bonilla WV, Fadejeva J, Kreutzfeldt M, Wagner I, Aparicio-Domingo P, Scarpellino L, Charmoy M, Utzschneider DT, Hagedorn C, Lu M, Cornille K, Stauffer K, Kreppel F, Merkler D, Zehn D, Held W, Luther SA, Löhning M, and Pinschewer DD
- Subjects
- Animals, Mice, Alarmins metabolism, Interleukin-1 Receptor-Like 1 Protein metabolism, Lymphocytic choriomeningitis virus, Mice, Inbred C57BL, Persistent Infection, T Cell Transcription Factor 1 metabolism, CD8-Positive T-Lymphocytes, Interleukin-33 metabolism, Lymphocytic Choriomeningitis immunology
- Abstract
T cell factor 1 (Tcf-1) expressing CD8
+ T cells exhibit stem-like self-renewing capacity, rendering them key for immune defense against chronic viral infection and cancer. Yet, the signals that promote the formation and maintenance of these stem-like CD8+ T cells (CD8+ SL) remain poorly defined. Studying CD8+ T cell differentiation in mice with chronic viral infection, we identified the alarmin interleukin-33 (IL-33) as pivotal for the expansion and stem-like functioning of CD8+ SL as well as for virus control. IL-33 receptor (ST2)-deficient CD8+ T cells exhibited biased end differentiation and premature loss of Tcf-1. ST2-deficient CD8+ SL responses were restored by blockade of type I interferon signaling, suggesting that IL-33 balances IFN-I effects to control CD8+ SL formation in chronic infection. IL-33 signals broadly augmented chromatin accessibility in CD8+ SL and determined these cells' re-expansion potential. Our study identifies the IL-33-ST2 axis as an important CD8+ SL-promoting pathway in the context of chronic viral infection., Competing Interests: Declaration of interests D.D.P. is a founder, consultant, and shareholder of Hookipa Pharma Inc. commercializing arenavirus-based vector technology, and he as well as W.V.B., S.M.K., and D.M. are listed as inventor on corresponding patents., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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27. A buprenorphine depot formulation provides effective sustained post-surgical analgesia for 72 h in mouse femoral fracture models.
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Wolter A, Bucher CH, Kurmies S, Schreiner V, Konietschke F, Hohlbaum K, Klopfleisch R, Löhning M, Thöne-Reineke C, Buttgereit F, Huwyler J, Jirkof P, Rapp AE, and Lang A
- Subjects
- Animals, Female, Male, Mice, Disease Models, Animal, Drinking Water, Mice, Inbred C57BL, Pain Management methods, Tramadol pharmacology, Analgesia methods, Buprenorphine administration & dosage, Femoral Fractures surgery, Pain, Postoperative drug therapy, Pain, Postoperative etiology, Pain, Postoperative prevention & control
- Abstract
Adequate pain management is essential for ethical and scientific reasons in animal experiments and should completely cover the period of expected pain without the need for frequent re-application. However, current depot formulations of Buprenorphine are only available in the USA and have limited duration of action. Recently, a new microparticulate Buprenorphine formulation (BUP-Depot) for sustained release has been developed as a potential future alternative to standard formulations available in Europe. Pharmacokinetics indicate a possible effectiveness for about 72 h. Here, we investigated whether the administration of the BUP-Depot ensures continuous and sufficient analgesia in two mouse fracture models (femoral osteotomy) and could, therefore, serve as a potent alternative to the application of Tramadol via the drinking water. Both protocols were examined for analgesic effectiveness, side effects on experimental readout, and effects on fracture healing outcomes in male and female C57BL/6N mice. The BUP-Depot provided effective analgesia for 72 h, comparable to the effectiveness of Tramadol in the drinking water. Fracture healing outcome was not different between analgesic regimes. The availability of a Buprenorphine depot formulation for rodents in Europe would be a beneficial addition for extended pain relief in mice, thereby increasing animal welfare., (© 2023. The Author(s).)
- Published
- 2023
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28. Insights into osteoarthritis development from single-cell RNA sequencing of subchondral bone.
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Shen P and Löhning M
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- Humans, Chondrocytes, Sequence Analysis, RNA, Osteoarthritis diagnosis, Osteoarthritis genetics
- Abstract
Competing Interests: Competing interests: None declared.
- Published
- 2022
- Full Text
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29. Optimization of chondrocyte isolation from human articular cartilage to preserve the chondrocyte transcriptome.
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Shen P, Wu P, Maleitzke T, Reisener MJ, Heinz GA, Heinrich F, Durek P, Gwinner C, Winkler T, Pumberger M, Perka C, Mashreghi MF, and Löhning M
- Abstract
The isolation of chondrocytes from human articular cartilage for single-cell RNA sequencing requires extensive and prolonged tissue digestion at 37 C. Modulations of the transcriptional activity likely take place during this period such that the transcriptomes of isolated human chondrocytes no longer match their original status in vivo . Here, we optimized the human chondrocyte isolation procedure to maximally preserve the in vivo transcriptome. Cartilage tissues were transferred into a hypoxia chamber (4% O
2 ) immediately after being removed from OA patients and minced finely. Collagenase II at concentrations of 0.02%, 0.1%, 0.25%, 0.5%, 1%, and 2% was applied for 0.5, 1, 2, 4, and 18 h to digest the minced tissue. Actinomycin D (ActD) was added to test its capacity in stabilizing the transcriptome. Cell yield, viability, cell size, and transcriptome were determined using counter chamber, flow cytometry, and RNA sequencing (RNA-seq). Collagenase II at 2% concentration released small chondrocytes from cartilage matrix during the first digestion hour and started to release large cells thereafter, reaching a complete release at 4 h. During 4-h digestions, collagenase II at 2% and 1% but not at lower concentrations yielded maximal release also of the large chondrocyte population. RNA-seq analysis revealed that a 4-h digestion period with 1% or 2% collagenase II plus Actinomycin D optimally preserved the transcriptome. Thus, this study provides an isolation protocol for single chondrocytes from human articular cartilage optimized for transcriptome preservation and RNA-seq analysis., Competing Interests: The authors declare that research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shen, Wu, Maleitzke, Reisener, Heinz, Heinrich, Durek, Gwinner, Winkler, Pumberger, Perka, Mashreghi and Löhning.)- Published
- 2022
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30. [The DRFZ-a pioneer in research on the interaction between immune and stromal cells during de- and regeneration of the musculoskeletal system].
- Author
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Löhning M, Shen P, Dzamukova M, Durán-Hernández N, Roodselaar J, Hauser AE, Fiedler A, Niesner RA, Gaber T, and Buttgereit F
- Subjects
- Female, Glucocorticoids, Humans, Inflammation, Stromal Cells, Cartilage, Articular, Osteoarthritis
- Abstract
Rheumatoid arthritis and osteoarthritis are two related chronic diseases of the musculoskeletal system which are particularly pronounced in the region of joints and bones. Their pathogeneses are associated with chronic inflammation, which can disrupt homeostasis in bones and articular cartilage. Degradation products deriving from articular cartilage can contribute to the exacerbation of inflammation in the joint region. Mechanical stimuli and blood vessels also play a central role in both the regulation of bone growth as well as in the regeneration of bone tissue. Not only chronic inflammatory processes but also hormonal changes after menopause or undesired effects of glucocorticoid therapy have an influence on the balance between bone resorption and deposition, by promoting the former and reducing the latter. This results in decreased bone quality and, in some cases, considerable loss of bone or osteoporosis. An in-depth understanding of these processes at the molecular, cellular, and tissue level, as well as of the changes present in chronic inflammatory diseases, has been the focus of research at the German Rheumatism Research Center (Deutsches Rheuma-Forschungszentrum, DRFZ) since its foundation. Based on an improved understanding of these mechanisms, the DRFZ aims to develop improved prevention and treatment strategies with effects even in early disease stages., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)
- Published
- 2022
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31. Dissecting the dynamic transcriptional landscape of early T helper cell differentiation into Th1, Th2, and Th1/2 hybrid cells.
- Author
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Burt P, Peine M, Peine C, Borek Z, Serve S, Floßdorf M, Hegazy AN, Höfer T, Löhning M, and Thurley K
- Subjects
- Cell Differentiation genetics, Hybrid Cells, Lymphocyte Activation, Th1 Cells, Th2 Cells
- Abstract
Selective differentiation of CD4+ T helper (Th) cells into specialized subsets such as Th1 and Th2 cells is a key element of the adaptive immune system driving appropriate immune responses. Besides those canonical Th-cell lineages, hybrid phenotypes such as Th1/2 cells arise in vivo , and their generation could be reproduced in vitro . While master-regulator transcription factors like T-bet for Th1 and GATA-3 for Th2 cells drive and maintain differentiation into the canonical lineages, the transcriptional architecture of hybrid phenotypes is less well understood. In particular, it has remained unclear whether a hybrid phenotype implies a mixture of the effects of several canonical lineages for each gene, or rather a bimodal behavior across genes. Th-cell differentiation is a dynamic process in which the regulatory factors are modulated over time, but longitudinal studies of Th-cell differentiation are sparse. Here, we present a dynamic transcriptome analysis following Th-cell differentiation into Th1, Th2, and Th1/2 hybrid cells at 3-h time intervals in the first hours after stimulation. We identified an early bifurcation point in gene expression programs, and we found that only a minority of ~20% of Th cell-specific genes showed mixed effects from both Th1 and Th2 cells on Th1/2 hybrid cells. While most genes followed either Th1- or Th2-cell gene expression, another fraction of ~20% of genes followed a Th1 and Th2 cell-independent transcriptional program associated with the transcription factors STAT1 and STAT4. Overall, our results emphasize the key role of high-resolution longitudinal data for the characterization of cellular phenotypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Burt, Peine, Peine, Borek, Serve, Floßdorf, Hegazy, Höfer, Löhning and Thurley.)
- Published
- 2022
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32. Mechanical forces couple bone matrix mineralization with inhibition of angiogenesis to limit adolescent bone growth.
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Dzamukova M, Brunner TM, Miotla-Zarebska J, Heinrich F, Brylka L, Mashreghi MF, Kusumbe A, Kühn R, Schinke T, Vincent TL, and Löhning M
- Subjects
- Adolescent, Bone Development, Bone Matrix, Extracellular Matrix Proteins, Humans, Ion Channels, Morphogenesis, Phosphoproteins, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-2, Calcification, Physiologic, Neovascularization, Physiologic, Stress, Mechanical
- Abstract
Bone growth requires a specialised, highly angiogenic blood vessel subtype, so-called type H vessels, which pave the way for osteoblasts surrounding these vessels. At the end of adolescence, type H vessels differentiate into quiescent type L endothelium lacking the capacity to promote bone growth. Until now, the signals that switch off type H vessel identity and thus limit adolescent bone growth have remained ill defined. Here we show that mechanical forces, associated with increased body weight at the end of adolescence, trigger the mechanoreceptor PIEZO1 and thereby mediate enhanced production of the kinase FAM20C in osteoblasts. FAM20C, the major kinase of the secreted phosphoproteome, phosphorylates dentin matrix protein 1, previously identified as a key factor in bone mineralization. Thereupon, dentin matrix protein 1 is secreted from osteoblasts in a burst-like manner. Extracellular dentin matrix protein 1 inhibits vascular endothelial growth factor signalling by preventing phosphorylation of vascular endothelial growth factor receptor 2. Hence, secreted dentin matrix protein 1 transforms type H vessels into type L to limit bone growth activity and enhance bone mineralization. The discovered mechanism may suggest new options for the treatment of diseases characterised by aberrant activity of bone and vessels such as osteoarthritis, osteoporosis and osteosarcoma., (© 2022. The Author(s).)
- Published
- 2022
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33. Menstrual blood-derived mesenchymal stromal cells efficiently ameliorate experimental autoimmune encephalomyelitis by inhibiting T cell activation in mice.
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Li Y, Gao H, Brunner TM, Hu X, Yan Y, Liu Y, Qiao L, Wu P, Li M, Liu Q, Yang F, Lin J, Löhning M, and Shen P
- Subjects
- Animals, Cell Differentiation, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Th17 Cells, Encephalomyelitis, Autoimmune, Experimental, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells
- Abstract
Background: Immunosuppressive properties grant mesenchymal stromal cells (MSCs) promising potential for treating autoimmune diseases. As autologous MSCs suffer from limited availability, the readily available allogeneic MSCs isolated from menstrual blood (MB-MSCs) donated by young, healthy individuals offer great potential. Here, we evaluate the therapeutic potential of MB-MSCs as ready-to-use allo-MSCs in multiple sclerosis, an autoimmune disease developed by the activation of myelin sheath-reactive Th1 and Th17 cells, by application in its animal model experimental autoimmune encephalomyelitis (EAE)., Methods: We assessed the therapeutic effect of MB-MSCs transplanted via either intravenous (i.v.) or intraperitoneal (i.p.) route in EAE in comparison with umbilical cord-derived MSCs (UC-MSCs). We used histology to assess myelin sheath integrity and infiltrated immune cells in CNS and flow cytometry to evaluate EAE-associated inflammatory T cells and antigen-presenting cells in lymphoid organs., Results: We observed disease-ameliorating effects of MB-MSCs when transplanted at various stages of EAE (day - 1, 6, 10, and 19), via either i.v. or i.p. route, with a potency comparable to UC-MSCs. We observed reduced Th1 and Th17 cell responses in mice that had received MB-MSCs via either i.v. or i.p. injection. The repressed Th1 and Th17 cell responses were associated with a reduced frequency of plasmacytoid dendritic cells (pDCs) and a suppressed co-stimulatory capacity of pDCs, cDCs, and B cells., Conclusions: Our data demonstrate that the readily available MB-MSCs significantly reduced the disease severity of EAE upon transplantation. Thus, they have the potential to be developed as ready-to-use allo-MSCs in MS-related inflammation., (© 2022. The Author(s).)
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- 2022
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34. CD39 and CD326 Are Bona Fide Markers of Murine and Human Plasma Cells and Identify a Bone Marrow Specific Plasma Cell Subpopulation in Lupus.
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Dang VD, Mohr E, Szelinski F, Le TA, Ritter J, Hinnenthal T, Stefanski AL, Schrezenmeier E, Ocvirk S, Hipfl C, Hardt S, Cheng Q, Hiepe F, Löhning M, Dörner T, and Lino AC
- Subjects
- Animals, Antibodies, Antinuclear, Antibody-Producing Cells, Biomarkers metabolism, Humans, Immunoglobulin M, Mice, Bone Marrow metabolism, Plasma Cells metabolism
- Abstract
Antibody-secreting cells (ASCs) contribute to immunity through production of antibodies and cytokines. Identification of specific markers of ASC would allow selective targeting of these cells in several disease contexts. Here, we performed an unbiased, large-scale protein screening, and identified twelve new molecules that are specifically expressed by murine ASCs. Expression of these markers, particularly CD39, CD81, CD130, and CD326, is stable and offers an improved resolution for ASC identification. We accessed their expression in germ-free conditions and in T cell deficient mice, showing that at least in part their expression is controlled by microbial- and T cell-derived signals. Further analysis of lupus mice revealed the presence of a subpopulation of LAG-3
- plasma cells, co-expressing high amounts of CD39 and CD326 in the bone marrow. This population was IgM+ and correlated with IgM anti-dsDNA autoantibodies in sera. Importantly, we found that CD39, CD81, CD130, and CD326 are also expressed by human peripheral blood and bone marrow ASCs. Our data provide innovative insights into ASC biology and function in mice and human, and identify an intriguing BM specific CD39++ CD326++ ASC subpopulation in autoimmunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dang, Mohr, Szelinski, Le, Ritter, Hinnenthal, Stefanski, Schrezenmeier, Ocvirk, Hipfl, Hardt, Cheng, Hiepe, Löhning, Dörner and Lino.)- Published
- 2022
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35. MIF does only marginally enhance the pro-regenerative capacities of DFO in a mouse-osteotomy-model of compromised bone healing conditions.
- Author
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Lang A, Stefanowski J, Pfeiffenberger M, Wolter A, Damerau A, Hemmati-Sadeghi S, Haag R, Hauser AE, Löhning M, Duda GN, Hoff P, Schmidt-Bleek K, Gaber T, and Buttgereit F
- Subjects
- Animals, Bone Regeneration, Deferoxamine pharmacology, Deferoxamine therapeutic use, Fracture Healing, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Intramolecular Oxidoreductases pharmacology, Mice, Osteotomy, Macrophage Migration-Inhibitory Factors pharmacology, Osteogenesis
- Abstract
The initial phase of fracture healing is crucial for the success of bone regeneration and is characterized by an inflammatory milieu and low oxygen tension (hypoxia). Negative interference with or prolongation of this fine-tuned initiation phase will ultimately lead to a delayed or incomplete healing such as non-unions which then requires an effective and gentle therapeutic intervention. Common reasons include a dysregulated immune response, immunosuppression or a failure in cellular adaptation to the inflammatory hypoxic milieu of the fracture gap and a reduction in vascularizing capacity by environmental noxious agents (e.g. rheumatoid arthritis or smoking). The hypoxia-inducible factor (HIF)-1α is responsible for the cellular adaptation to hypoxia, activating angiogenesis and supporting cell attraction and migration to the fracture gap. Here, we hypothesized that stabilizing HIF-1α could be a cost-effective and low-risk prevention strategy for fracture healing disorders. Therefore, we combined a well-known HIF-stabilizer - deferoxamine (DFO) - and a less known HIF-enhancer - macrophage migration inhibitory factor (MIF) - to synergistically induce improved fracture healing. Stabilization of HIF-1α enhanced calcification and osteogenic differentiation of MSCs in vitro. In vivo, only the application of DFO without MIF during the initial healing phase increased callus mineralization and vessel formation in a preclinical mouse-osteotomy-model modified to display a compromised healing. Although we did not find a synergistically effect of MIF when added to DFO, our findings provide additional support for a preventive strategy towards bone healing disorders in patients with a higher risk by accelerating fracture healing using DFO to stabilize HIF-1α., (Copyright © 2021. Published by Elsevier Inc.)
- Published
- 2022
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36. Vaccine-elicited CD4 T cells prevent the deletion of antiviral B cells in chronic infection.
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Narr K, Ertuna YI, Fallet B, Cornille K, Dimitrova M, Marx AF, Martin K, Abreu Mota T, Künzli M, Schreiner D, Brunner TM, Kreutzfeldt M, Wagner I, Geier F, Bestmann L, Löhning M, Merkler D, King CG, and Pinschewer DD
- Subjects
- Animals, Antibodies, Viral immunology, Antigen Presentation immunology, Antiviral Agents immunology, Cells, Cultured, Germinal Center immunology, Inflammation immunology, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus immunology, Memory B Cells immunology, Mice, Proto-Oncogene Proteins c-bcl-6 immunology, T-Lymphocytes, Helper-Inducer immunology, Th1 Cells immunology, Vaccination methods, B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, Persistent Infection immunology, Vaccines immunology, Virus Diseases immunology
- Abstract
Chronic viral infections subvert protective B cell immunity. An early type I interferon (IFN-I)-driven bias to short-lived plasmablast differentiation leads to clonal deletion, so-called "decimation," of antiviral memory B cells. Therefore, prophylactic countermeasures against decimation remain an unmet need. We show that vaccination-induced CD4 T cells prevented the decimation of naïve and memory B cells in chronically lymphocytic choriomeningitis virus (LCMV)-infected mice. Although these B cell responses were largely T independent when IFN-I was blocked, preexisting T help assured their sustainability under conditions of IFN-I-driven inflammation by instructing a germinal center B cell transcriptional program. Prevention of decimation depended on T cell-intrinsic Bcl6 and Tfh progeny formation. Antigen presentation by B cells, interactions with antigen-specific T helper cells, and costimulation by CD40 and ICOS were also required. Importantly, B cell-mediated virus control averted Th1-driven immunopathology in LCMV-challenged animals with preexisting CD4 T cell immunity. Our findings show that vaccination-induced Tfh cells represent a cornerstone of effective B cell immunity to chronic virus challenge, pointing the way toward more effective B cell-based vaccination against persistent viral diseases.
- Published
- 2021
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37. Systematic review on the reporting accuracy of experimental details in publications using mouse femoral fracture models.
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Wolter A, Rapp AE, Durst MS, Hildebrand L, Löhning M, Buttgereit F, Schmidt-Bleek K, Jirkof P, and Lang A
- Subjects
- Animals, Bone Regeneration, Humans, Mice, Pain, Pain Management, Periodicals as Topic standards, Disease Models, Animal, Femoral Fractures diagnostic imaging
- Abstract
The outcomes of animal experiments can be influenced by a variety of factors. Thus, precise reporting is necessary to provide reliable and reproducible data. Initiatives such as the ARRIVE guidelines have been enrolled during the last decade to provide a road map for sufficient reporting. To understand the sophisticated process of bone regeneration and to develop new therapeutic strategies, small rodents, especially mice, are frequently used in bone healing research. Since many factors might influence the results from those studies, we performed a systematic literature search from 2010 to 2019 to identify studies involving mouse femoral fracture models (stable fixation) and evaluated the reporting of general and model-specific experimental details. 254 pre-selected publications were systematically analyzed, showing a high reporting accuracy for the used mouse strain, the age or developmental stage and sex of mice as well as model-specific information on fixation methods and fracturing procedures. However, reporting was more often insufficient in terms of mouse substrains and genetic backgrounds of genetically modified mice, body weight, hygiene monitoring/immune status of the animal, anesthesia, and analgesia. Consistent and reliable reporting of experimental variables in mouse fracture surgeries will improve scientific quality, enhance animal welfare, and foster translation into the clinic., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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38. Mast Cells Modulate Antigen-Specific CD8 + T Cell Activation During LCMV Infection.
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Hackler Y, Siebenhaar F, Löhning M, Maurer M, and Muñoz M
- Subjects
- Animals, CD8-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes virology, Cell Communication, Cell Proliferation, Cells, Cultured, Cytokines metabolism, Dendritic Cells metabolism, Dendritic Cells virology, Disease Models, Animal, Heparin-binding EGF-like Growth Factor genetics, Heparin-binding EGF-like Growth Factor metabolism, Host-Pathogen Interactions, Lymphocytic Choriomeningitis metabolism, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus pathogenicity, Mast Cells metabolism, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Signal Transduction, Mice, Antigens, Viral immunology, CD8-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Lymphocyte Activation, Lymphocytic Choriomeningitis immunology, Lymphocytic choriomeningitis virus immunology, Mast Cells immunology
- Abstract
Mast cells (MCs), strategically localized at mucosal surfaces, provide first-line defense against pathogens and shape innate and adaptive immune responses. Recent studies have shown that MCs are involved in pathogenic responses to several viruses including herpes simplex viruses, dengue virus, vaccinia virus and influenza virus. However, the underlying mechanisms of MCs in the activation of CD8
+ T cells during viral infections are not fully understood. Therefore, we investigate the role of MCs in the development of virus-specific CD8+ T cell responses using the well-characterized murine lymphocytic choriomeningitis virus (LCMV) model and the transgenic MasTRECK mice that contain the human diphtheria toxin receptor as an inducible MC-deficient model. Here, we report that MCs are essential for the activation and expansion of virus-specific CD8+ T cells. After MC depletion and subsequent intradermal LCMV infection, the CD8+ T cell effector phenotype and antiviral cytokine production were impaired at the peak of infection (day 8 p.i.). Importantly, MC-deficient mice were unable to control the infection and exhibited significantly higher viral loads in the spleen and in the ear draining lymph nodes compared to that of wild type control mice. In the absence of MCs, dendritic cell (DC) activation was impaired upon LCMV infection. In addition, type-I interferon (IFN) levels in the serum and in the spleen of MC-deficient mice were reduced during the first days of infection. Interestingly, depletion of MCs after intradermal LCMV infection did not impair virus-specific CD8+ T cell expansion, activation or antiviral cytokine production. In summary, our results indicate that MCs play a pivotal role in the activation and antiviral functions of CD8+ T cells through proper DC activation. A better understanding of the impact of MCs on CD8+ T cell responses is mandatory to improve antiviral immune responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hackler, Siebenhaar, Löhning, Maurer and Muñoz.)- Published
- 2021
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39. Th2 cells lacking T-bet suppress naive and memory T cell responses via IL-10.
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Muñoz M, Hegazy AN, Brunner TM, Holecska V, Marek RM, Fröhlich A, and Löhning M
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 prevention & control, Down-Regulation, Epitopes immunology, Lymphocyte Activation immunology, Lymphocytic Choriomeningitis immunology, Lymphocytic Choriomeningitis virology, Lymphocytic choriomeningitis virus immunology, Mice, Inbred C57BL, Mice, Knockout, Mice, Immunologic Memory, Interleukin-10 metabolism, T-Box Domain Proteins deficiency, T-Box Domain Proteins metabolism, Th2 Cells immunology
- Abstract
Exacerbated immune responses and loss of self-tolerance lead to the development of autoimmunity and immunopathology. Novel therapies to target autoreactive T cells are still needed. Here, we report that Th2-polarized T cells lacking the transcription factor T-bet harbor strong immunomodulatory potential and suppress antigen-specific CD8
+ T cells via IL-10. Tbx21-/- Th2 cells protected mice against virus-induced type 1 diabetes development and suppressed not only naive but also memory CD8+ T cell responses. IL-10-producing, but not IL-10-deficient Tbx21-/- Th2 cells down-regulated costimulatory molecules on dendritic cells and reduced their IL-12 production after lymphocytic choriomeningitis virus infection. Impaired dendritic cell activation hindered effector and cytotoxic CD8+ T cell development after infection. These findings indicate that Tbx21-/- Th2 cells strongly suppress proinflammatory responses of naive and memory T cells via IL-10. Thus, in vivo IL-10-secreting Th2 cells could harbor a therapeutic potential for the treatment of T cell-mediated inflammatory disorders., Competing Interests: The authors declare no competing interest.- Published
- 2021
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40. NK cell receptor NKG2D enforces proinflammatory features and pathogenicity of Th1 and Th17 cells.
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Babic M, Dimitropoulos C, Hammer Q, Stehle C, Heinrich F, Sarsenbayeva A, Eisele A, Durek P, Mashreghi MF, Lisnic B, Van Snick J, Löhning M, Fillatreau S, Withers DR, Gagliani N, Huber S, Flavell RA, Polic B, and Romagnani C
- Subjects
- Animals, Arthritis, Experimental genetics, Arthritis, Experimental pathology, Cytokines genetics, Cytokines immunology, Encephalomyelitis, Autoimmune, Experimental genetics, Encephalomyelitis, Autoimmune, Experimental pathology, Inflammation genetics, Inflammation immunology, Inflammation pathology, Mice, Mice, Knockout, NK Cell Lectin-Like Receptor Subfamily K genetics, T-Box Domain Proteins genetics, T-Box Domain Proteins immunology, Th1 Cells pathology, Th17 Cells pathology, Arthritis, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental immunology, NK Cell Lectin-Like Receptor Subfamily K immunology, Th1 Cells immunology, Th17 Cells immunology
- Abstract
NKG2D is a danger sensor expressed on different subsets of innate and adaptive lymphocytes. Despite its established role as a potent activator of the immune system, NKG2D-driven regulation of CD4+ T helper (Th) cell-mediated immunity remains unclear. In this study, we demonstrate that NKG2D modulates Th1 and proinflammatory T-bet+ Th17 cell effector functions in vitro and in vivo. In particular, NKG2D promotes higher production of proinflammatory cytokines by Th1 and T-bet+ Th17 cells and reinforces their transcription of type 1 signature genes, including Tbx21. Conditional deletion of NKG2D in T cells impairs the ability of antigen-specific CD4+ T cells to promote inflammation in vivo during antigen-induced arthritis and experimental autoimmune encephalomyelitis, indicating that NKG2D is an important target for the amelioration of Th1- and Th17-mediated chronic inflammatory diseases., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2020 Babic et al.)
- Published
- 2020
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41. Enhanced Cell Division Is Required for the Generation of Memory CD4 T Cells to Migrate Into Their Proper Location.
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Sarkander J, Hojyo S, Mursell M, Yamasaki Y, Wu TY, Tumes DJ, Miyauchi K, Tran CL, Zhu J, Löhning M, Hutloff A, Mashreghi MF, Kubo M, Radbruch A, and Tokoyoda K
- Subjects
- Animals, CD28 Antigens genetics, CD28 Antigens immunology, CD4-Positive T-Lymphocytes cytology, Cell Division genetics, Integrin alpha2 genetics, Integrin alpha2 immunology, Interleukin-2 genetics, Interleukin-2 immunology, Interleukin-2 Receptor beta Subunit genetics, Interleukin-2 Receptor beta Subunit immunology, Mice, Mice, Knockout, Receptors, CCR7 genetics, Receptors, CCR7 immunology, T-Box Domain Proteins genetics, T-Box Domain Proteins immunology, Bone Marrow immunology, CD4-Positive T-Lymphocytes immunology, Cell Division immunology, Cell Movement immunology, Immunologic Memory
- Abstract
CD4 T cell memory is fundamental for long-lasting immunity and effective secondary responses following infection or vaccination. We have previously found that memory CD4 T cells specific for systemic antigens preferentially reside in the bone marrow (BM) and arise from splenic CD49b
+ T-bet+ CD4 T cells. However, how BM-homing memory precursors are generated during an immune reaction is unknown. We show here that BM memory precursors are generated via augmented rates of cell division throughout a primary immune response. Treatment with the cytostatic drug cyclophosphamide or blockade of the CD28/B7 co-stimulatory pathway at the beginning of the contraction phase abrogates the generation of BM memory precursors. We determine that, following a critical number of cell divisions, memory precursors downregulate CCR7 and upregulate IL-2Rβ, indicating that loss of CCR7 and gain of IL-2 signal are required for the migration of memory precursors toward the BM., (Copyright © 2020 Sarkander, Hojyo, Mursell, Yamasaki, Wu, Tumes, Miyauchi, Tran, Zhu, Löhning, Hutloff, Mashreghi, Kubo, Radbruch and Tokoyoda.)- Published
- 2020
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42. Single-cell transcriptomes of murine bone marrow stromal cells reveal niche-associated heterogeneity.
- Author
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Addo RK, Heinrich F, Heinz GA, Schulz D, Sercan-Alp Ö, Lehmann K, Tran CL, Bardua M, Matz M, Löhning M, Hauser AE, Kruglov A, Chang HD, Durek P, Radbruch A, and Mashreghi MF
- Subjects
- Animals, B-Cell Activating Factor genetics, Cells, Cultured, Cytokines genetics, Hematopoietic Stem Cells cytology, Interleukin-15 genetics, Interleukin-7 genetics, Mesenchymal Stem Cells cytology, Mice, Mice, Inbred C57BL, Sequence Analysis, RNA methods, Bone Marrow physiology, Bone Marrow Cells cytology, Stromal Cells cytology, Transcriptome genetics
- Abstract
Bone marrow (BM) stromal cells are important in the development and maintenance of cells of the immune system. Using single cell RNA sequencing, we here explore the functional and phenotypic heterogeneity of individual transcriptomes of 1167 murine BM mesenchymal stromal cells. These cells exhibit a tremendous heterogeneity of gene expression, which precludes the identification of defined subpopulations. However, according to the expression of 108 genes involved in the communication of stromal cells with hematopoietic cells, we have identified 14 non-overlapping subpopulations, with distinct cytokine or chemokine gene expression signatures. With respect to the maintenance of subsets of immune memory cells by stromal cells, we identified distinct subpopulations expressing Il7, Il15 and Tnfsf13b. Together, this study provides a comprehensive dissection of the BM stromal heterogeneity at the single cell transcriptome level and provides a basis to understand their lifestyle and their role as organizers of niches for the long-term maintenance of immune cells., (© 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2019
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43. Memory CD8 + T Cell Protection From Viral Reinfection Depends on Interleukin-33 Alarmin Signals.
- Author
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Baumann C, Fröhlich A, Brunner TM, Holecska V, Pinschewer DD, and Löhning M
- Subjects
- Animals, Lymphocytic choriomeningitis virus immunology, Mice, Inbred C57BL, Signal Transduction immunology, Alarmins immunology, Immunologic Memory immunology, Interleukin-33 immunology, Lymphocytic Choriomeningitis immunology, T-Lymphocytes, Cytotoxic immunology
- Abstract
Memory CD8
+ cytotoxic T lymphocytes (CTLs) can protect against viral reinfection. However, the signals driving rapid memory CTL reactivation have remained ill-defined. Viral infections can trigger the release of the alarmin interleukin-33 (IL-33) from non-hematopoietic cells. IL-33 signals through its unique receptor ST2 to promote primary effector expansion and activation of CTLs. Here, we show that the transcription factor STAT4 regulated the expression of ST2 on CTLs in vitro and in vivo in primary infections with lymphocytic choriomeningitis virus (LCMV). In the primary antiviral response, IL-33 enhanced effector differentiation and antiviral cytokine production in a CTL-intrinsic manner. Further, using sequential adoptive transfers of LCMV-specific CD8+ T cells, we deciphered the IL-33 dependence of circulating memory CTLs at various stages of their development. IL-33 was found dispensable for the formation and maintenance of memory CTLs, and its absence during priming did not affect their recall response. However, in line with the CTL-boosting role of IL-33 in primary LCMV infections, circulating memory CTLs required IL-33 for efficient secondary expansion, enhanced effector functions, and virus control upon challenge infection. Thus, beyond their effector-promoting activity in primary immune reactions, innate alarmin signals also drive memory T cell recall responses, which has implications for immunity to recurrent diseases.- Published
- 2019
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44. Manipulation of the balance between Th2 and Th2/1 hybrid cells affects parasite nematode fitness in mice.
- Author
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Affinass N, Zhang H, Löhning M, Hartmann S, and Rausch S
- Subjects
- Animals, Cell Differentiation, Cells, Cultured, Cytokines metabolism, Interferon-gamma genetics, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Spleen parasitology, Interferon-gamma metabolism, Intestines immunology, Nematospiroides dubius physiology, Spleen immunology, Strongylida Infections immunology, Th1 Cells immunology, Th2 Cells immunology
- Abstract
T-helper type 2 (Th2) responses are central to the control of helminth infections, but sensitive to opposing cytokine signals favoring Th1 priming. We previously reported on GATA-3
+ T-bet+ Th2/1 hybrid cell differentiation in helminth mono-infections, resulting in a substantial proportion of cells coproducing IFN-γ next to Th2 cytokines. Here, we demonstrate Th2/1 cells as the major source of parasite-specific IFN-γ production in acute and chronic infections with the enteric nematode Heligmosomoides polygyrus. Th2/1 cells differentiated from naive precursors and accumulated in spleen and intestine of infected mice, resulting in increased systemic and mucosal IFN-γ production. IFN-γ supplementation early during infection supported Th2/1 differentiation, associated with elevated parasite fecundity and the maintenance of high worm burdens in the chronic stage of infection, whereas mice lacking IFN-γ signals generated poor Th2/1 responses and restricted parasite fecundity more efficiently. These findings suggest that Th2/1 hybrid responses take part in immune regulation during helminth infection and restrain effective anti-helminth immunity., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2018
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45. T H 17 cells express ST2 and are controlled by the alarmin IL-33 in the small intestine.
- Author
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Pascual-Reguant A, Bayat Sarmadi J, Baumann C, Noster R, Cirera-Salinas D, Curato C, Pelczar P, Huber S, Zielinski CE, Löhning M, Hauser AE, and Esplugues E
- Subjects
- Animals, Cells, Cultured, Homeostasis, Interleukin-1 Receptor-Like 1 Protein genetics, Interleukin-10 metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction, Alarmins metabolism, Inflammation immunology, Interleukin-1 Receptor-Like 1 Protein metabolism, Interleukin-33 metabolism, Intestine, Small immunology, T-Lymphocytes, Regulatory immunology, Th17 Cells immunology
- Abstract
T
H 17 cells are major drivers of inflammation and involved in several autoimmune diseases. Tissue inflammation is a beneficial host response to infection, but it can also contribute to autoimmunity. The crosstalk between a tissue and the immune system during an inflammatory response is key for preserving tissue integrity and restoring physiological processes. However, how the inflamed tissue regulates the magnitude of an immune response by controlling pro-inflammatory T cells is not well characterized so far. Here we show that TH 17 cells accumulating in the small intestine upon inflammation express the IL-33 receptor (ST2) and intestinal epithelial cells (IEC) are the main source of the alarmin interleukin-33 (IL-33). We show that pro-inflammatory TH 17 cells acquire a regulatory phenotype with immunosuppressive properties in response to IL-33. Absence of ST2 signaling promotes the secretion of pro-inflammatory cytokines by TH 17 cells and dampens the secretion of IL-10. Our results provide new insights into the mechanisms by which IEC, via IL-33/ST2 axis, may control pro-inflammatory TH 17 cells in the small intestine to sustain homeostasis.- Published
- 2017
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46. Th2/1 Hybrid Cells Occurring in Murine and Human Strongyloidiasis Share Effector Functions of Th1 Cells.
- Author
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Bock CN, Babu S, Breloer M, Rajamanickam A, Boothra Y, Brunn ML, Kühl AA, Merle R, Löhning M, Hartmann S, and Rausch S
- Subjects
- Adolescent, Adult, Aged, Animals, CD4-Positive T-Lymphocytes immunology, Cytokines blood, Female, GATA3 Transcription Factor metabolism, Humans, Hybrid Cells metabolism, Immunoglobulin E blood, Immunoglobulin G blood, India, Interferon-gamma, Interleukin-13 blood, Interleukin-4 blood, Interleukin-5 blood, Intestine, Small pathology, Lung pathology, Lymph Nodes pathology, Male, Mice, Middle Aged, Spleen pathology, Strongyloides ratti genetics, Strongyloidiasis pathology, Th1 Cells metabolism, Th2 Cells metabolism, Young Adult, Hybrid Cells immunology, Strongyloides ratti pathogenicity, Strongyloidiasis immunology, Th1 Cells immunology, Th2 Cells immunology
- Abstract
Infections by the soil-transmitted threadworm Strongyloides stercoralis affect 30-100 million people worldwide, predominantly in tropic and sub-tropic regions. Here we assessed the T helper cell phenotypes in threadworm-infected patients and experimental murine infections with focus on CD4
+ T cells co-expressing markers of Th2 and Th1 differentiation. We show that mice infected with the close relative S. ratti generate strong Th2 responses characterized by the expansion of CD4+ GATA-3+ cells expressing IL-4/-5/-13 in blood, spleen, gut-draining lymph nodes, lung and gut tissue. In addition to conventional Th2 cells, significantly increased frequencies of GATA-3+ T-bet+ Th2/1-hybrid cells were detected in all organs and co-expressed Th2- and Th1-cytokines at intermediate levels. Assessing the phenotype of blood-derived CD4+ T cells from South Indian patients infected with S. stercoralis and local uninfected control donors we found that GATA-3 expressing Th2 cells were significantly increased in the patient cohort, coinciding with elevated eosinophil and IgE/IgG4 levels. A fraction of IL-4+ CD4+ T cells simultaneously expressed IFN-γ hence displaying a Th2/1 hybrid phenotype. In accordance with murine Th2/1 cells, human Th2/1 cells expressed intermediate levels of Th2 cytokines. Contrasting their murine counterparts, human Th2/1 hybrids were marked by high levels of IFN-γ and rather low GATA-3 expression. Assessing the effector function of murine Th2/1 cells in vitro we found that Th2/1 cells were qualified for driving the classical activation of macrophages. Furthermore, Th2/1 cells shared innate, cytokine-driven effector functions with Th1 cells. Hence, the key findings of our study are that T helper cells with combined characteristics of Th2 and Th1 cells are integral to immune responses of helminth-infected mice, but also occur in helminth-infected humans and we suggest that Th2/1 cells are poised for the instruction of balanced immune responses during nematode infections.- Published
- 2017
- Full Text
- View/download PDF
47. Replicating viral vector platform exploits alarmin signals for potent CD8 + T cell-mediated tumour immunotherapy.
- Author
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Kallert SM, Darbre S, Bonilla WV, Kreutzfeldt M, Page N, Müller P, Kreuzaler M, Lu M, Favre S, Kreppel F, Löhning M, Luther SA, Zippelius A, Merkler D, and Pinschewer DD
- Subjects
- Animals, Antigens, Neoplasm immunology, Cancer Vaccines therapeutic use, Cell Line, Tumor, Dendritic Cells immunology, Gene Expression Profiling, Genetic Engineering, Genetic Vectors genetics, Genetic Vectors immunology, Genetic Vectors therapeutic use, HEK293 Cells, Humans, Interleukin-33 genetics, Interleukin-33 immunology, Lymphocyte Activation immunology, Mesocricetus, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, Neoplasms immunology, Tumor Microenvironment immunology, Vaccines, Live, Unattenuated immunology, Virus Replication genetics, Virus Replication immunology, Xenograft Model Antitumor Assays, Alarmins immunology, Cancer Vaccines immunology, Immunotherapy methods, Lymphocytic choriomeningitis virus genetics, Neoplasms therapy, T-Lymphocytes, Cytotoxic immunology
- Abstract
Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTL
eff ) responses. Conversely, the induction of protective tumour-specific CTLeff and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTLeff responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTLeff influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy.- Published
- 2017
- Full Text
- View/download PDF
48. Synovial Fibroblasts Selectively Suppress Th1 Cell Responses through IDO1-Mediated Tryptophan Catabolism.
- Author
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Tykocinski LO, Lauffer AM, Bohnen A, Kaul NC, Krienke S, Tretter T, Adam I, Mohapatra SR, Saikali P, Löhning M, Neidhart M, Gay S, Oezen I, Platten M, Opitz CA, and Lorenz HM
- Subjects
- Cell Differentiation immunology, Chromatography, High Pressure Liquid, Coculture Techniques, Fibroblasts metabolism, Humans, Immunoblotting, Indoleamine-Pyrrole 2,3,-Dioxygenase immunology, Lymphocyte Activation immunology, Osteoarthritis immunology, Polymerase Chain Reaction, Synovial Membrane immunology, Th17 Cells immunology, Th2 Cells immunology, Tryptophan immunology, Arthritis, Rheumatoid immunology, Fibroblasts immunology, Indoleamine-Pyrrole 2,3,-Dioxygenase metabolism, Th1 Cells immunology, Tryptophan metabolism
- Abstract
The development of rheumatoid arthritis (RA) is linked to functional changes in synovial fibroblasts (SF) and local infiltration of T lymphocytes. Fibroblasts possess the capacity to suppress T cell responses, although the molecular mechanisms of this suppression remain incompletely understood. In this study, we aimed to define the mechanisms by which noninflammatory SF modulate Th cell responses and to determine the immunosuppressive efficacy of RASF. Hence, the influence of SF from osteoarthritis or RA patients on total Th cells or different Th cell subsets of healthy donors was analyzed in vitro. We show that SF strongly suppressed the proliferation of Th cells and the secretion of IFN-γ in a cell contact-independent manner. In cocultures of SF and Th cells, tryptophan was completely depleted within a few days, resulting in eukaryotic initiation factor 2α phosphorylation, TCRζ-chain downregulation, and proliferation arrest. Blocking IDO1 activity completely restored Th cell proliferation, but not IFN-γ production. Interestingly, only the proliferation of Th1 cells, but not of Th2 or Th17 cells, was affected. Finally, RASF had a significantly lower IDO1 expression and a weaker Th cell suppressive capacity compared with osteoarthritis SF. We postulate that the suppression of Th cell growth by SF through tryptophan catabolism may play an important role in preventing inappropriate Th cell responses under normal conditions. However, expansion of Th17 cells that do not induce IDO1-mediated suppression and the reduced capacity of RASF to restrict Th cell proliferation through tryptophan metabolism may support the initiation and propagation of synovitis in RA patients., (Copyright © 2017 by The American Association of Immunologists, Inc.)
- Published
- 2017
- Full Text
- View/download PDF
49. Spatiotemporally restricted arenavirus replication induces immune surveillance and type I interferon-dependent tumour regression.
- Author
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Kalkavan H, Sharma P, Kasper S, Helfrich I, Pandyra AA, Gassa A, Virchow I, Flatz L, Brandenburg T, Namineni S, Heikenwalder M, Höchst B, Knolle PA, Wollmann G, von Laer D, Drexler I, Rathbun J, Cannon PM, Scheu S, Bauer J, Chauhan J, Häussinger D, Willimsky G, Löhning M, Schadendorf D, Brandau S, Schuler M, Lang PA, and Lang KS
- Subjects
- Animals, CD8-Positive T-Lymphocytes immunology, Cell Line, Tumor, Humans, Lymphocyte Activation immunology, Lymphocytic choriomeningitis virus physiology, Mice, Inbred C57BL, Monocytes metabolism, Neoplasms blood supply, Oncolytic Viruses metabolism, Programmed Cell Death 1 Receptor metabolism, Arenavirus physiology, Immunologic Surveillance, Interferon Type I metabolism, Neoplasms immunology, Neoplasms virology, Virus Replication physiology
- Abstract
Immune-mediated effector molecules can limit cancer growth, but lack of sustained immune activation in the tumour microenvironment restricts antitumour immunity. New therapeutic approaches that induce a strong and prolonged immune activation would represent a major immunotherapeutic advance. Here we show that the arenaviruses lymphocytic choriomeningitis virus (LCMV) and the clinically used Junin virus vaccine (Candid#1) preferentially replicate in tumour cells in a variety of murine and human cancer models. Viral replication leads to prolonged local immune activation, rapid regression of localized and metastatic cancers, and long-term disease control. Mechanistically, LCMV induces antitumour immunity, which depends on the recruitment of interferon-producing Ly6C
+ monocytes and additionally enhances tumour-specific CD8+ T cells. In comparison with other clinically evaluated oncolytic viruses and to PD-1 blockade, LCMV treatment shows promising antitumoural benefits. In conclusion, therapeutically administered arenavirus replicates in cancer cells and induces tumour regression by enhancing local immune responses.- Published
- 2017
- Full Text
- View/download PDF
50. B Cells Negatively Regulate the Establishment of CD49b(+)T-bet(+) Resting Memory T Helper Cells in the Bone Marrow.
- Author
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Hojyo S, Sarkander J, Männe C, Mursell M, Hanazawa A, Zimmel D, Zhu J, Paul WE, Fillatreau S, Löhning M, Radbruch A, and Tokoyoda K
- Abstract
During an immune reaction, some antigen-experienced CD4 T cells relocate from secondary lymphoid organs (SLOs) to the bone marrow (BM) in a CD49b-dependent manner and reside and rest there as professional memory CD4 T cells. However, it remains unclear how the precursors of BM memory CD4 T cells are generated in the SLOs. While several studies have so far shown that B cell depletion reduces the persistence of memory CD4 T cells in the spleen, we here show that B cell depletion enhances the establishment of memory CD4 T cells in the BM and that B cell transfer conversely suppresses it. Interestingly, the number of antigen-experienced CD4 T cells in the BM synchronizes the number of CD49b(+)T-bet(+) antigen-experienced CD4 T cells in the spleen. CD49b(+)T-bet(+) antigen-experienced CD4 T cells preferentially localize in the red pulp area of the spleen and the BM in a T-bet-independent manner. We suggest that B cells negatively control the generation of CD49b(+)T-bet(+) precursors of resting memory CD4 T cells in the spleen and may play a role in bifurcation of activated effector and resting memory CD4 T cell lineages.
- Published
- 2016
- Full Text
- View/download PDF
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