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Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center–Follicular Helper T Cells
Author(s) -
Schmiel Shirdi E.,
Kalekar Lokesh A.,
Zhang Na,
Blankespoor Thomas W.,
Robinson Londyn J.,
Mueller Daniel L.
Publication year - 2019
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.40796
Subject(s) - germinal center , immunology , arthritis , t cell , isotype , biology , medicine , antibody , b cell , monoclonal antibody , immune system
Objective CD 4 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 CD 4 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 CD 4 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 CD 4 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 CD 4 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 CD 4 T cells may be promising therapeutic targets for interfering with potentially dangerous autoreactive GC ‐Tfh cell differentiation.