The endogenous repertoire harbors self-reactive CD4 + T cell clones that adopt a follicular helper T cell-like phenotype at steady state.

The T cell repertoire of healthy mice and humans harbors self-reactive CD4 + conventional T (T conv ) cells capable of inducing autoimmunity. Using T cell receptor profiling paired with in vivo clonal analysis of T cell differentiation, we identified T conv cell clones that are recurrently enriched in non-lymphoid organs following ablation of Foxp3 + regulatory T (T reg ) cells. A subset of these clones was highly proliferative in the lymphoid organs at steady state and exhibited overt reactivity to self-ligands displayed by dendritic cells, yet were not purged by clonal deletion. These clones spontaneously adopted numerous hallmarks of follicular helper T (T FH ) cells, including expression of Bcl6 and PD-1, exhibited an elevated propensity to localize within B cell follicles at steady state, and produced interferon-γ in non-lymphoid organs following sustained T reg cell depletion. Our work identifies a naturally occurring population of self-reactive T FH -like cells and delineates a previously unappreciated fate for self-specific T conv cells.