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

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Science Immunology  20 Jul 2018:
Vol. 3, Issue 25, eaas9103
DOI: 10.1126/sciimmunol.aas9103

Signal strength seals fate

T cell differentiation into effector and memory T cell subsets is influenced by T cell receptor (TCR) signals. Snook et al. examine how TCR signals influence CD4+ T cell differentiation using a panel of cloned TCRs that recognize the same MHC II–restricted epitope of lymphocytic choriomeningitis virus. Strong TCR signals were associated with TH1 differentiation, whereas lower TCR signal strength corresponded with follicular helper T cell and memory T cell differentiation. Low CD25 expression by early effector T cells also predicted memory differentiation, although CD25 expression levels were not predictive of recall responses. Enhanced TCR signaling via knockdown of SHP-1 favored TH1 over Tfh and memory T cell differentiation. These results indicated that stronger TCR signaling promotes terminal effector TH1 differentiation.


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 κB. After viral infection, strong TCR signals corresponded to T helper cell (TH1) 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 CD25lo effector cells that displayed decreased TCR signaling in vivo. Nevertheless, memory T cells derived from either CD25lo or CD25hi 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 CD25lo 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 TH1 effector and memory cells. We conclude that strong TCR signals during early T cell activation favor terminal TH1 differentiation over long-term TH1 and T follicular helper cell memory responses.

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