Objective: CD4 germinal center (GC)–follicular helper T (Tfh) cells are important in the pathogenesis of autoimmune arthritis. Previous studies have shown that adenosine 2a receptor (A2aR; Adora2a) signaling can divert CD4 T cells away from the GC-Tfh cell lineage during the primary response to foreign antigens. This study was undertaken to examine the effects of A2aR signaling on CD4 T cells during the recognition of self antigen in a murine model of autoimmune arthritis. Methods: Wild-type and Adora2a-deficient mouse KRN T cell receptor–transgenic CD4 T cells specific for glucose-6-phosphate isomerase (GPI)/I-A g7 were transferred into immunodeficient Tcra −/− I-A g7 –expressing mice to induce arthritis. Recipients were then treated with either the selective A2aR agonist CGS-21680 (CGS) or phosphate buffered saline alone. Severity of disease, autoantibody titers, KRN T cell numbers and phenotype, and GPI-specific isotype class–switched plasmablasts were tracked. Results: CGS treatment inhibited the development of arthritis and differentiation of KRN GC-Tfh cells, blocked the appearance of high-affinity GPI-specific and IgG1 isotype class–switched polyclonal plasmablasts, and led to a reduction in serum titers of anti-GPI IgG1. In addition, therapeutic administration of CGS after the onset of arthritis blocked further disease progression in association with reductions in the number of KRN GC-Tfh cells and anti-GPI IgG1 serum titers. Conclusion: Strong A2aR signaling diverts autoreactive CD4 T cell differentiation away from the GC-Tfh cell lineage, thus reducing help for the differentiation of dangerous autoreactive B cells that promote arthritis. These data in a mouse model of autoimmune arthritis suggest that A2aR and its downstream signaling pathways in CD4 T cells may be promising therapeutic targets for interfering with potentially dangerous autoreactive GC-Tfh cell differentiation.
|Original language||English (US)|
|Number of pages||11|
|Journal||Arthritis and Rheumatology|
|State||Published - May 2019|
Bibliographical notePublisher Copyright:
© 2018, American College of Rheumatology