Aberrant T follicular helper cells generated by T_H17 cell plasticity in the gut promote extraintestinal autoimmunity

Much remains unknown regarding T follicular helper 17 (T_FH17) cells commonly found in autoimmune patients. We previously showed that (and here ask why) egress of gut segmented filamentous bacteria (SFB)-induced T_FH cells from Peyer's patches (PP) to systemic sites promotes arthritis. We found splenic T_FH17 cells are gut derived. Functional analyses using fate-mapping mice revealed a c-Maf-dependent and SFB-induced T_H17-to-T_FH cell reprogramming that dominantly occurs in PPs. Unlike conventional T_FH cells, T_H17-derived T_FH cells are highly migratory and atypically concentrated in the dark zone of germinal centers (GCs). Compared to conventional T_FH cells, T_H17-derived T_FH cells express higher levels of T_FH-associated functional molecules and more robustly conjugate with B cells. Gain- and loss-of-function studies demonstrated their dominance in promoting GC B cells and arthritis. Notably, murine gut T_H17-derived T_FH signatures exist in rheumatoid arthritis patients. Thus, gut T cell plasticity generates atypical, potent T_FH cells promoting systemic autoimmunity.