Follicular CD8 T cells in autoantibody-mediated disease.

Abstract

Abstract The role of CD8 T cells, unlike CD4 T cells, in antibody-mediated autoimmune disease remains largely unexplored. CD8 T cells act both in a cytotoxic CD8 T cell role and helper-like role during autoimmunity. CD4 T follicular cells (Tfh), interact with B cells to promote proliferation, activation and antibody class switching. In autoimmunity, dysregulated self-reactive CD4 Tfh can promote autoantibody production. We have identified a novel population of CD8 T cells within the germinal center that resembles CD4 Tfh cells during systemic autoantibody-mediated disease. IL-2 deficient (IL-2-KO) mice develop systemic autoantibody-mediated disease including autoantibodies against red blood cells (RBC) resulting in autoimmune hemolytic anemia. We show that the absence of either CD4 or CD8 T cells prevents the development of anti-RBC antibodies and reduces lymphoproliferation in IL-2-KO mice. RNA-sequencing of IL-2-KO CD8 T cells revealed an increase in the expression of genes associated with CD4 Tfh lineages (Bcl-6, CXCR5, PD-1, ICOS and IL-21) compared with wild type (WT) CD8 T cells. Flow cytometry of expanded CXCR5+PD-1+ CD4 Tfh cells and CXCR5+PD-1+ CD8 T follicular (Tfc) cells confirms the protein expression of these Tfh markers and the production of IL-21 in IL-2-KO late stage disease (day 18–21). In vitro culture of IL-2-KO CD8 Tfc cells induced antibody class switching in WT B cells at levels similar to that induced by adjuvant-induced WT CD4 Tfh cells. In comparison to CXCR5- PD-1-CD8 T cells, CD8 Tfc cells expressed higher levels of CD40L. Our results indicate that CD8 T cells contribute to autoimmune disease in part through differentiation into follicular T cells that function to induce B cell differentiation and antibody class-switch.