{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zinzow-Kramer WM"],"funding":["NIA NIH HHS","NIAMS NIH HHS"],"pagination":["671-683"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12917752"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["6(9)"],"pubmed_abstract":["T cells experience varying intensities of tonic or basal TCR signaling in response to self-peptides presented by MHC (self-pMHC) in vivo. We analyzed four subpopulations of mouse naive CD4<sup>+</sup> cells that express different levels of Nur77-GFP and Ly6C, surrogate markers that positively and inversely correlate with the strength of tonic TCR signaling, respectively. Adoptive transfer studies suggest that relatively weak or strong Nur77-GFP intensity in thymocytes tends to be maintained in mature T cells. Two-dimensional affinity measurements were lowest for Nur77-GFP<sup>lo</sup>Ly6C<sup>+</sup> cells and highest for Nur77-GFP<sup>hi</sup>Ly6C<sup>-</sup> cells, highlighting a positive correlation between apparent TCR affinity and tonic TCR signal strength. Despite experiencing the strongest tonic TCR signaling, Nur77-GFP<sup>hi</sup>Ly6C<sup>-</sup> cells were least responsive to multiple concentrations of a cognate or suboptimal pMHC. Gene expression analyses suggest that Nur77-GFP<sup>hi</sup>Ly6C<sup>-</sup> cells induce a gene expression program that has similarities with that of acutely stimulated T cells. However, strong tonic TCR signaling also correlates with increased expression of genes with inhibitory functions, including coinhibitory receptors. Similarly, assay for transposase-accessible chromatin with sequencing analyses suggested that increased tonic TCR signal strength correlated with increased chromatin accessibility associated with genes that have positive and inhibitory roles in T cell activation. Strikingly, Nur77-GFP<sup>hi</sup>Ly6C<sup>-</sup> cells exhibited differential accessibility within regions of <i>Cd200r1</i> and <i>Tox</i> that were similar in location to differentially accessible regions previously identified in exhausted CD8<sup>+</sup> T cells. We propose that constitutive strong tonic TCR signaling triggers adaptations detectable at both the transcriptional and epigenetic levels, ultimately contributing to the tuning of T cell responsiveness."],"journal":["ImmunoHorizons"],"pubmed_title":["Strong Basal/Tonic TCR Signals Are Associated with Negative Regulation of Naive CD4&lt;sup&gt;+&lt;/sup&gt; T Cells."],"pmcid":["PMC12917752"],"funding_grant_id":["K01 AG065485","K01 AR065481"],"pubmed_authors":["Evavold BD","Scharer CD","Eggert J","Kolawole EM","Zinzow-Kramer WM","Au-Yeung BB"],"additional_accession":[]},"is_claimable":false,"name":"Strong Basal/Tonic TCR Signals Are Associated with Negative Regulation of Naive CD4&lt;sup&gt;+&lt;/sup&gt; T Cells.","description":"T cells experience varying intensities of tonic or basal TCR signaling in response to self-peptides presented by MHC (self-pMHC) in vivo. We analyzed four subpopulations of mouse naive CD4<sup>+</sup> cells that express different levels of Nur77-GFP and Ly6C, surrogate markers that positively and inversely correlate with the strength of tonic TCR signaling, respectively. Adoptive transfer studies suggest that relatively weak or strong Nur77-GFP intensity in thymocytes tends to be maintained in mature T cells. Two-dimensional affinity measurements were lowest for Nur77-GFP<sup>lo</sup>Ly6C<sup>+</sup> cells and highest for Nur77-GFP<sup>hi</sup>Ly6C<sup>-</sup> cells, highlighting a positive correlation between apparent TCR affinity and tonic TCR signal strength. Despite experiencing the strongest tonic TCR signaling, Nur77-GFP<sup>hi</sup>Ly6C<sup>-</sup> cells were least responsive to multiple concentrations of a cognate or suboptimal pMHC. Gene expression analyses suggest that Nur77-GFP<sup>hi</sup>Ly6C<sup>-</sup> cells induce a gene expression program that has similarities with that of acutely stimulated T cells. However, strong tonic TCR signaling also correlates with increased expression of genes with inhibitory functions, including coinhibitory receptors. Similarly, assay for transposase-accessible chromatin with sequencing analyses suggested that increased tonic TCR signal strength correlated with increased chromatin accessibility associated with genes that have positive and inhibitory roles in T cell activation. Strikingly, Nur77-GFP<sup>hi</sup>Ly6C<sup>-</sup> cells exhibited differential accessibility within regions of <i>Cd200r1</i> and <i>Tox</i> that were similar in location to differentially accessible regions previously identified in exhausted CD8<sup>+</sup> T cells. We propose that constitutive strong tonic TCR signaling triggers adaptations detectable at both the transcriptional and epigenetic levels, ultimately contributing to the tuning of T cell responsiveness.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Sep","modification":"2026-07-16T11:55:18.351Z","creation":"2026-07-09T10:52:02.641Z"},"accession":"S-EPMC12917752","cross_references":{"pubmed":["36100367"],"doi":["10.4049/immunohorizons.2200051"]}}