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

Naive 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 naive 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(HI) 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 naive CD4(+) cells.