Pathogenic follicular CD8 T cells promote autoimmune disease.
The contribution of CD8 T cells to autoimmune disease remains in debate. We show autoimmune CD8 T cells which induce antibody class switching and plasma cell differentiation act synergistically with CD4 T cells in promoting germinal center reactions. We have identified CXCR5+PD-1+ CD8 effector T (CD8 T follicular; Tfc) cells, within the germinal center, that expand during late autoimmune disease progression. We show that CD8 Tfc cells transcriptionally and phenotypically resemble CD4 T follicular helper (Tfh) cells in multiple models of spontaneous autoantibody-mediated disease including IL-2 deficient (IL-2-KO), scurfy and MRL/MpJ-FASlpr mice. CD8 Tfc cells maintain the capacity to produce significant amounts of cytotoxic proteins granzyme B, CD107a and TNFα, and helper-associated cytokines IL-21, IFNγ and IL-4. Functionally, CD8 Tfc cells promote cytokine-mediated antibody class switch using mechanisms largely independent of IFNγ or IL-21. When adoptively transferred CD8 Tfc cells in combination with CD4 Tfh cell promote autoantibody production. Our results indicate that CD8 Tfc cells contribute to autoimmune disease synergistically with CD4 Tfh cells to induce B cell class switching and autoantibodies during disease progression. Autoimmune disease is a novel immune setting during which CXCR5+ CD8 T cells develop beyond situations of chronic viral infection and cancer. Thus, pathogenic CD8 T cells influence germinal center reactions and promote autoimmune responses.