Follicular CD8 T cells function in germinal center reactions to promote autoantibody-mediated disease.

Abstract

Abstract CD8 T cell function, unlike CD4 T cells, in antibody-mediated autoimmune disease remains largely unexplored. CD8 T cells act as either cytotoxic or helper-like cells during autoimmunity. CD4 T follicular cells (Tfh) interact with B cells to promote proliferation, activation and antibody class switching. CXCR5+PD-1hi CD8 T follicular (Tfc) cells localized within the germinal center resemble CD4 Tfh cells in multiple models of spontaneous autoantibody-mediated disease, including IL-2 deficient (IL-2-KO), Scurfy and MRL/MpJ-FASlprmice. CD4 and CD8 T cells activated with NP-KLH synergistically induce B cell class switching to IgG1 IgG2a, IgG2b, and IgG3 in vivo. RNA-sequencing of IL-2-KO CD8 Tfc and IL-2-KO CD4 Tfh cells identified 478 differentially expressed genes unique to CD8 Tfc cells. These data revealed an increased expression of genes associated with CD8 Tfc cell function including il21, ifnγ, prf1. IL-21 produced by CD4 Tfh cells but not CD8 Tfc cells promotes total IgG class switching demonstrated by in vitro cultures of activated autoimmune CD8 Tfc or CD4 Tfh cell supernatant incubated with IL-21R-KO B cells. IFNγ x IL-2-KO mice develop both CD4 Tfh and CD8 Tfc cells correlating with autoantibody production. In vitro culture assays demonstrate that IFNγ produced by CD8 Tfc cells promotes B cell class switching to. Our results indicate that CD8 Tfc cells contribute to autoimmune disease synergistically with CD4 Tfh cells to induce B cell differentiation and antibody class-switch. We are continuing to explore the unique functions of CD8 Tfc cells on germinal center interactions.