Session Type: ACR Concurrent Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: CD4 germinal center (GC)-T follicular helper (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. Therefore, we examined the effects of A2aR signaling on CD4 T cells during the recognition of a self-antigen using a mouse model of autoimmune arthritis.
Methods: Wild type and Adora2a-deficient KRN TCR-transgenic CD4 T cells specific for glucose-6-phosphate isomerase (GPI)/I-Ag7 self-peptide were transferred into immunodeficient Tcra–/– I-Ag7-expressing mice to induce arthritis, and then recipients were treated with either the selective A2aR agonist CGS-21680 (CGS) or PBS vehicle 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 arthritis development and KRN Bcl6hi CXCR5hi GC-Tfh cell differentiation, blocked the appearance of high affinity GPI-specific and IgG1 isotype class-switched polyclonal plasmablasts, and led to a reduction in anti-GPI IgG1 titers. Additionally, therapeutic administration of CGS after the onset of arthritis blocked further disease progression in association with reduced KRN GC-Tfh cell numbers and anti-GPI IgG1 titers. The therapeutic effects of CGS treatment were lost when the Adora2a gene was deleted only from the KRN T cells.
Conclusion: Strong A2aR signaling diverts autoreactive CD4 T cell differentiation away from the GC-Tfh lineage, thus reducing help for the differentiation of dangerous autoreactive B cells that promote arthritis. Therefore, our data suggest that the A2aR and its downstream signaling pathways in CD4 T cells may be promising therapeutic targets to interfere with autoreactive GC-Tfh cell differentiation.
To cite this abstract in AMA style:Schmiel S, Mueller DL. Adenosine 2a Receptor Signals Act to Limit Autoimmune Arthritis By Inhibiting Pathogenic Germinal Center T Follicular Helper (GC-Tfh) Cells [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/adenosine-2a-receptor-signals-act-to-limit-autoimmune-arthritis-by-inhibiting-pathogenic-germinal-center-t-follicular-helper-gc-tfh-cells/. Accessed May 25, 2019.
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