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

The T cell repertoire of healthy mice and humans harbors self-reactive CD4+ conventional T (Tconv) cells capable of inducing autoimmunity. Using T cell receptor (TCR) profiling paired with in vivo clonal analysis of T cell differentiation, we identified Tconv cell clones that are recurrently enriched in non-lymphoid organs following ablation of Foxp3+ regulatory T cells. A subset of these clones were 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 T follicular helper (Tfh) cells, including expression of Bcl6 and PD-1, yet failed to produce common effector cytokines at baseline. The homeostasis of polyclonal Tconv cells displaying similar features was critically dependent on B cells. Our work identifies a naturally occurring population of self-reactive Tfh-like cells and delineates a previously unappreciated fate for self-specific Tconv cells. Examination of differential gene expression by 2 TCR "retrogenic" CD4+ T cell clones. Cells of interest were FACS sorted from pooled spleen and lymph nodes of C57BL/6J mice that received bone marrow progenitors retrovirally transduced with a TCRa expression construct.