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

Sci Immunol. 2018 Jul 20;3(25):eaas9103. doi: 10.1126/sciimmunol.aas9103.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / physiology*
  • Cell Differentiation / physiology*
  • Cell Line
  • Chlorocebus aethiops
  • Cricetinae
  • Female
  • Flow Cytometry
  • Homeodomain Proteins / genetics
  • Interleukin-2 Receptor alpha Subunit
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell / physiology*


  • Homeodomain Proteins
  • Interleukin-2 Receptor alpha Subunit
  • Receptors, Antigen, T-Cell
  • RAG-1 protein