CXCR5 + PD-1 + follicular helper CD8 T cells control B cell tolerance.

Many autoimmune diseases are characterized by the production of autoantibodies. The current view is that CD4 ⁺ T follicular helper (Tfh) cells are the main subset regulating autoreactive B cells. Here we report a CXCR5 ⁺ PD1 ⁺ Tfh subset of CD8 ⁺ T cells whose development and function are negatively modulated by Stat5. These CD8 ⁺ Tfh cells regulate the germinal center B cell response and control autoantibody production, as deficiency of Stat5 in CD8 T cells leads to an increase of CD8 ⁺ Tfh cells, resulting in the breakdown of B cell tolerance and concomitant autoantibody production. CD8 ⁺ Tfh cells share similar gene signatures with CD4 ⁺ Tfh, and require CD40L/CD40 and TCR/MHCI interactions to deliver help to B cells. Our study thus highlights the diversity of follicular T cell subsets that contribute to the breakdown of B-cell tolerance.