Strong basal/tonic TCR signals are associated with negative regulation of naive CD4+ T cells

Abstract

Tonic TCR signaling occurs constitutively in response to self-peptides presented by MHC (pMHC). Tonic TCR signal intensity correlates with Nur77-GFP reporter transgene expression. A broad range of Nur77-GFP is first detectable in post-selection thymocytes and persists in mature T cells. Nur77-GFPHI Ly6C- CD4+ T cells experience the strongest tonic TCR signaling and exhibit functional hypo-responsiveness to foreign pMHC stimulation. Gene expression analyses suggest similarities between the programs induced by strong tonic TCR signaling and T cell activation. However, the strongest tonic TCR signals also appear to induce expression of negative regulators, including coinhibitory receptors. Analysis of chromatin accessibility similarly suggest that strong tonic TCR signaling correlates with differentially higher accessibility of over 3000 chromatin regions in or near genes that encode positive and negative regulators of T cell activation. We propose that very strong tonic TCR signaling induces mechanisms of negative feedback to recalibrate T cell sensitivity.