Purinergic receptors are attractive therapeutic targets that can regulate several facets of the immune system. This dissertation examines the role of purinergic G protein-coupled Adenosine 2a (A2aR) receptors in regulating adaptive immune responses during the primary response to vaccination and during self-antigen recognition in the context autoimmunity. Administration of A2aR agonist CGS-21680 (CGS) can alter CD4 T cell differentiation by diverting helper T cells away from a germinal center follicular helper T cells (GC-Tfh) linage that promotes the survival, differentiation, isotype class-switching, and affinity maturation of B cells. Although GC-Tfh cells are beneficial during the clearance of certain pathogens, they also can be detrimental if they malfunction and mistakenly provide help to pathogenic self-specific B cells. Previous studies suggest that A2aRs acts as a barrier to autoimmunity by limiting inflammatory responses. Our studies support this claim by showing that prophylactic treatment with CGS blocks autoimmune arthritis. A2aR agonist treatment caused a reduction in the frequency and number of pathogenic GC-Tfh cells and isotype class-switched plasmablasts that respond to autoantigen. CGS treatment of mice after the early onset of mild arthritis also had a therapeutic benefit and blocked disease progression. CGS therapy reduced the number pathogenic GC-Tfh cells and autoantibody titers, suggesting that A2aR downstream signals may serve to limit dangerous GC-Tfh cell effectors that contribute to autoimmune disease manifestations, thus making it an attractive target for future immunotherapies.
University of Minnesota Ph.D. dissertation. May 2017. Major: Microbiology, Immunology and Cancer Biology. Advisors: Daniel Mueller, Michael Farrar. 1 computer file (PDF); ix, 92 pages.
Analysis of Adenosine 2a Receptors During the Immune Recognition of Foreign and Self-Antigens.
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