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

The pathways controlling T follicular helper (T-FH) cell development are only partially understood. Allen and colleagues demonstrate the importance of the T cell receptor, with low tonic signaling promoting T(FH)cell development and high tonic signaling opposing it. T follicular helper (T-FH) 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(FH)cell-fate decision, but a critical aspect of the TCR has been overlooked: tonic TCR signaling. We hypothesized that tonic signaling influences early T(FH)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(FH)cell differentiation. Polyclonal T cells paralleled these findings, with naive Nur77 expression distinguishing T(FH)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(FH)cell development. Our findings elucidate a central role for tonic TCR signaling in early T(FH)cell-lineage decisions.