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

• Published in: Science immunology Vol. 3; no. 25
• Main Authors: Snook, Jeremy P, Kim, Chulwoo, Williams, Matthew A
• Format: Journal Article
• Language: English
• Published: United States 20.07.2018
• Subjects: Animals; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - physiology; Cell Differentiation - physiology; Cell Line; Cercopithecus aethiops; Cricetinae; Female; Flow Cytometry; Homeodomain Proteins - genetics; Interleukin-2 Receptor alpha Subunit; Male; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Antigen, T-Cell - physiology
• ISSN: 2470-9468
• 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 (T 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 effector cells that displayed decreased TCR signaling in vivo. Nevertheless, memory T cells derived from either CD25 or CD25 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 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 1 effector and memory cells. We conclude that strong TCR signals during early T cell activation favor terminal T 1 differentiation over long-term T 1 and T follicular helper cell memory responses.