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.