Adaptation by naïve CD4 T cells to self-antigen-dependent TCR signaling induces functional heterogeneity and tolerance.

Proc Natl Acad Sci U S A

Department of Medicine, Division of Immunology, Lowance Center for Human Immunology, Emory University, Atlanta, GA 30322;

Published: July 2019

Naïve CD4 T cells experience weak T cell receptor (TCR) signals induced by self-peptides presented by MHC II. To investigate how these "basal" TCR signals influence responses to agonist TCR ligand stimulation, we analyzed naïve CD4 cells expressing varying amounts of CD5, Ly6C, and Nur77-GFP, markers that reflect the strength of basal TCR signaling. Phenotypic analyses indicate that the broadest range of basal TCR signal strength can be visualized by a combination of Nur77-GFP and Ly6C. A range of basal TCR signaling is detectable even in populations that express identical TCRs. Whereas moderate basal TCR signal strength correlates with higher IL-2 secretion at early time points following TCR stimulation, weak basal TCR signaling correlated with higher IL-2 secretion at later time points. We identify a population of Nur77-GFP Ly6C cells that could not be reliably marked by either of CD5, Ly6C, or Nur77-GFP alone. These cells experience the strongest basal TCR signaling, consistently produce less IL-2, and express PD-1 and markers associated with anergy, such as Grail and Cbl-b. We propose that adaptation to the strength of basal TCR signaling drives the phenotypic and functional heterogeneity of naïve CD4 cells.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660790PMC
http://dx.doi.org/10.1073/pnas.1904096116DOI Listing

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