Pathogenic follicular CD8 T cells acquire diverse function during autoimmune disease

Abstract

Abstract CXCR5+ CD8 T cells identified within the germinal center have the capacity for diverse function in response to chronic antigen including chronic viral infection and cancer. CXCR5+ CD8 T cell pathogenic or protective function likely depends on the immunological setting. We have identified CXCR5+PD-1+ CD8 effector T cells (CD8 T follicular; Tfc) that resemble CD4 T follicular helper cells (Tfh) in multiple models of spontaneous autoantibody-mediated disease, including IL-2 deficient (IL-2-KO), scurfy and MRL/MpJ-FASlpr mice. Autoimmune CD8 T cells induce antibody class switching, and plasma cell differentiation synergistically with CD4 T cells in support of a novel function for CD8 Tfc cells during germinal center reactions. RNA-sequencing identified 478 differentially expressed genes unique to IL-2-KO CD8 Tfc compared to IL-2-KO CD4 Tfh including il21, Ifnγ, prf1. CD8 Tfc are polyfunctional and co-produce significant amounts of IL-21 and IL-4. Yet, only IL-21 produced by CD4 Tfh and not CD8 Tfc promotes total IgG class switching in in vitro cultures of activated T cell supernatant incubated with naïve B cells. CD8 Tfc supernatant deficient in IFNγ does not change antibody production. In addition to the helper profile, CD8 Tfc cells maintain the capacity to produce granzyme B, perforin, and CD107a when stimulated suggesting the possibility of direct cytolytic function within the germinal center. Our results indicate that CD8 Tfc cells contribute to autoimmune disease with CD4 Tfh cells to induce B cell responses and antibody class-switch. We will continue to investigate pathogenic CD8 Tfc cells in helper-like and cytotoxic roles during autoimmune disease. Funding from NIH R15 and the UC President’s Dissertation Year Fellowship