Strength of tonic T cell receptor signaling instructs T follicular helper cell-fate decisions.

T follicular helper (T) cells are critical in adaptive immune responses to pathogens and vaccines; however, what drives the initiation of their developmental program remains unclear. Studies suggest that a T cell antigen receptor (TCR)-dependent mechanism may be responsible for the earliest T cell-fate decision, but a critical aspect of the TCR has been overlooked: tonic TCR signaling. We hypothesized that tonic signaling influences early T cell development. Here, two murine TCR-transgenic CD4 T cells, LLO56 and LLO118, which recognize the same antigenic peptide presented on major histocompatibility complex molecules but experience disparate strengths of tonic signaling, revealed low tonic signaling promotes T cell differentiation. Polyclonal T cells paralleled these findings, with naive Nur77 expression distinguishing T cell potential. Two mouse lines were also generated to both increase and decrease tonic signaling strength, directly establishing an inverse relationship between tonic signaling strength and T cell development. Our findings elucidate a central role for tonic TCR signaling in early T cell-lineage decisions.