TY - JOUR
T1 - TCR signal strength controls the differentiation of CD4+ effector and memory T cells
AU - Snook, Jeremy P.
AU - Kim, Chulwoo
AU - Williams, Matthew A.
N1 - Funding Information:
We acknowledge T. Mosbruger and the Bioinformatics Shared Resource at the Huntsman Cancer Institute for assistance with deep sequencing and gene expression analysis. We acknowledge J. Marvin and the University of Utah Flow Cytometry Core Facility for assistance with the design and execution of cell purification by FACS. We acknowledge the NIH Tetramer Core Facility for providing reagents. Financial support for these studies was provided by the NIH (R01AI080830 and R01AI137248), the American Association of Immunologists Careers in Immunology Fellowship, and the University of Utah.
Publisher Copyright:
Copyright © 2018 The Authors, some rights reserved.
PY - 2018
Y1 - 2018
N2 - 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 B. 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.
AB - 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 B. 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.
UR - http://www.scopus.com/inward/record.url?scp=85053634155&partnerID=8YFLogxK
U2 - 10.1126/sciimmunol.aas9103
DO - 10.1126/sciimmunol.aas9103
M3 - Article
C2 - 30030369
AN - SCOPUS:85053634155
VL - 3
JO - Science immunology
JF - Science immunology
SN - 2470-9468
IS - 25
M1 - eaas9103
ER -