Division of Immunology, Lowance Center for Human Immunology, Department of Medicine, Emory University School of Medicine, Atlanta, GA.
Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT; and.
Immunohorizons. 2022 Sep 13;6(9):671-683. doi: 10.4049/immunohorizons.2200051.
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 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-GFPLy6C cells and highest for Nur77-GFPLy6C cells, highlighting a positive correlation between apparent TCR affinity and tonic TCR signal strength. Despite experiencing the strongest tonic TCR signaling, Nur77-GFPLy6C cells were least responsive to multiple concentrations of a cognate or suboptimal pMHC. Gene expression analyses suggest that Nur77-GFPLy6C 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-GFPLy6C cells exhibited differential accessibility within regions of and that were similar in location to differentially accessible regions previously identified in exhausted CD8 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.
T 细胞在体内对 MHC 呈递的自身肽（自 pMHC）产生不同强度的持续或基础 TCR 信号。我们分析了表达不同水平 Nur77-GFP 和 Ly6C 的四种小鼠幼稚 CD4 细胞亚群，这两种标志物分别与持续 TCR 信号的强度呈正相关和负相关。过继转移研究表明，胸腺细胞中相对较弱或较强的 Nur77-GFP 强度往往在成熟 T 细胞中得以维持。二维亲和力测量结果显示，Nur77-GFP^Ly6C 细胞的亲和力最低，而 Nur77-GFP^Ly6C 细胞的亲和力最高，这突出表明 TCR 亲和力与持续 TCR 信号强度之间存在正相关。尽管经历了最强的持续 TCR 信号，但 Nur77-GFP^Ly6C 细胞对多种浓度的同源或次优 pMHC 的反应性最低。基因表达分析表明，Nur77-GFP^Ly6C 细胞诱导了与急性刺激 T 细胞相似的基因表达程序。然而，强烈的持续 TCR 信号也与抑制功能基因的表达增加相关，包括共抑制受体。同样，转座酶可及染色质测序分析表明，持续 TCR 信号强度的增加与与 T 细胞激活中具有正性和抑制性作用的基因相关的染色质可及性增加相关。引人注目的是，Nur77-GFP^Ly6C 细胞在与先前在耗尽的 CD8 T 细胞中鉴定的差异可及区域相似的位置上表现出 和 区域内的差异可及性。我们提出，组成性强的持续 TCR 信号触发了在转录和表观遗传水平上都可检测到的适应性变化，最终导致 T 细胞反应性的调整。
