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

T follicular helper (Tfh) cells are critical in adaptive immune responses to pathogens and vaccines; however, what drives initiation of their developmental program remains unclear. Studies suggest a T cell antigen receptor (TCR)-dependent mechanism may be responsible for the earliest Tfh-fate decision, but a critical aspect of the TCR has been overlooked: tonic TCR signaling. We hypothesized tonic signaling influences early Tfh cell development. Here, two murine TCR-transgenic CD4(+) T cells, LLO56 and LLO118, that recognize the same antigenic-pMHC but experience disparate strengths of tonic signaling, revealed low tonic signaling promotes Tfh cell differentiation. Polyclonal T cells paralleled these findings, with naive Nur77 expression distinguishing Tfh 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 Tfh development. Our findings elucidate a central role for tonic TCR signaling in early Tfh-lineage decisions.