TCR signal strength controls the differentiation of CD4+ effector and memory T cells

CD4(+) T cell responses are composed of heterogeneous T cell receptor (TCR) signals that influence the acquisition of effector and memory characteristics. We sought to define early TCR-dependent activation events that control T cell differentiation. A polyclonal panel of TCRs specific for the same viral antigen demonstrated substantial variability in TCR signal strength, expression of CD25, and activation of nuclear factor of activated T cells and nuclear factor kappa B. After viral infection, strong TCR signals corresponded to T helper cell (T(H)1) differentiation, whereas T follicular helper cell and memory T cell differentiation were most efficient when TCR signals were comparatively lower. We observed substantial heterogeneity in TCR-dependent CD25 expression in vivo, and the vast majority of CD4(+) memory T cells were derived from CD25(Io) effector cells that displayed decreased TCR signaling in vivo. Nevertheless, memory T cells derived from either CD25(Io) or CD25(hi) effector cells responded vigorously to rechallenge, indicating that, although early clonal differences in CD25 expression predicted memory T cell numbers, they did not predict memory T cell function on a per cell basis. Gene transcription analysis demonstrated expression clustering based on CD25 expression and enrichment of transcripts associated with enhanced T follicular helper cell and memory development within CD25(Io) effector cells. Direct enhancement of TCR signaling via knockdown of Src homology region 2 domain-containing phosphatase 1, a tyrosine phosphatase that suppresses early TCR signaling events, favored the differentiation of T(H)1 effector and memory cells. We conclude that strong TCR signals during early T cell activation favor terminal T(H)1 differentiation over long-term T(H)1 and T follicular helper cell memory responses.