ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis

ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulat...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2018-05, Vol.200 (9), p.3067-3076
Main Authors: Panneton, Vincent, Bagherzadeh Yazdchi, Sahar, Witalis, Mariko, Chang, Jinsam, Suh, Woong-Kyung
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Animal models
Animals
Arthritis, Experimental - immunology
Arthritis, Rheumatoid - immunology
Collagen
Gene Knock-In Techniques
Glucose metabolism
Glycolysis
Inducible T-Cell Co-Stimulator Protein - immunology
Inflammation
Lymphocyte Activation - immunology
Lymphocytes
Lymphocytes T
Mice
Mice, Knockout
Rheumatoid arthritis
Signal transduction
Signal Transduction - immunology
Synovial fluid
T-Lymphocytes - immunology
Therapeutic applications
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Summary:ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, the Tyr -based SH2-binding motif of ICOS that is known to activate PI3K was critical for Ab production and expansion of inflammatory T cells. Furthermore, we found that Tyr -dependent ICOS signaling is important for maintenance of CIA in an Ab-independent manner. Importantly, we found that a small molecule inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA, suggesting an overlap between ICOS signaling, PI3K signaling, and glucose metabolism. Thus, we identified ICOS as a key costimulatory pathway that controls induction and maintenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1701305