Adenosine 2A Receptor Promotes Tolerance by Reducing Germinal Center Follicular Helper T cells and Pathogenic Class-Switched B cells

Abstract

Abstract Enhanced production of high affinity class-switched autoantibodies contributes to pathological symptoms of autoimmune diseases. Full penetrance of autoantibody production appears to rely on help from germinal center follicular helper T cells (GC TFH cells). GC TFH cells promote the survival, differentiation, isotype class switch, and affinity maturation of B cells. Previous studies have reported that activation of Adenosine receptor 2a (A2aR) downstream signaling negatively regulates adaptive immune responses by limiting the function of effector T cells. Recent work from our lab has demonstrated that the A2aR-specific agonist blocks autoimmune arthritis that is mediated by GPI-specific KRN CD4 T cells. A2aR agonist caused a reduction of GC TFH cells that respond to autoantigen. Consistent with this, GPI-specific humoral immune responses were also reduced in A2aR agonist treated mice. To establish if the effect of A2aR agonist treatment on GC TFH differentiation was T cell intrinsic, CD4-Cre A2aR-floxed B6 mice were immunized with a protein complex containing a CD4 T cell antigen (2W1S peptide) and B cell antigen (PE). Polyclonal 2W1S/I-Ab-specific CD4 T cells and PE-specific B cells were then monitored in the presence or absence of T cell-specific A2a receptors. Our data show that in the absence of T cell-specific A2a receptors, agonist treatment fails to influence GC TFH cell differentiation. Therefore, A2aR downstream signaling can be stimulated within autoreactive CD4 T cells during their encounter with self antigen, and can serve to limit the differentiation of dangerous GC TFH cell effectors. Ongoing experiments are working to identify the T cell-intrinsic mechanism by which A2aR signaling inhibits GC TFH cell generation.