强基础/强直TCR信号与初始CD4+ T细胞负调控相关

Q3 Medicine
Wendy M. Zinzow-Kramer, E. Kolawole, J. Eggert, B. Evavold, Christopher D. Scharer, Byron B. Au-Yeung
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引用次数: 5

摘要

在体内,T细胞经历不同强度的强韧或基础TCR信号传导,以响应由MHC(自我pmhc)呈递的自肽。我们分析了表达不同水平Nur77-GFP和Ly6C的小鼠幼稚CD4+细胞的四个亚群,这两个替代标记物分别与补性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强度在成熟T细胞中倾向于维持。二维亲和性测量在Nur77-GFPloLy6C+细胞中最低,而在Nur77-GFPhiLy6C -细胞中最高,这表明表观TCR亲和性与TCR信号强度呈正相关。尽管经历了最强的强直性TCR信号,但Nur77-GFPhiLy6C -细胞对多种浓度的同源或次优pMHC反应最小。基因表达分析表明,Nur77-GFPhiLy6C -细胞诱导的基因表达程序与急性刺激的T细胞相似。然而,强强直性TCR信号也与具有抑制功能的基因表达增加相关,包括共抑制受体。同样,对转座酶可接近染色质的测序分析表明,TCR信号强度的增加与染色质可接近性的增加相关,这些染色质可接近性与在T细胞活化中具有积极和抑制作用的基因相关。引人注目的是,Nur77-GFPhiLy6C -细胞在Cd200r1和Tox区域内表现出差异可达性,这些区域的位置与之前在耗尽的CD8+ T细胞中发现的差异可达性区域相似。我们提出,本构性强强直性TCR信号触发在转录和表观遗传水平上可检测到的适应性,最终有助于T细胞反应性的调节。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Strong Basal/Tonic TCR Signals Are Associated with Negative Regulation of Naive CD4+ T Cells
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-GFPloLy6C+ cells and highest for Nur77-GFPhiLy6C− cells, highlighting a positive correlation between apparent TCR affinity and tonic TCR signal strength. Despite experiencing the strongest tonic TCR signaling, Nur77-GFPhiLy6C− cells were least responsive to multiple concentrations of a cognate or suboptimal pMHC. Gene expression analyses suggest that Nur77-GFPhiLy6C− 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-GFPhiLy6C− cells exhibited differential accessibility within regions of Cd200r1 and Tox 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.
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来源期刊
CiteScore
3.70
自引率
0.00%
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0
审稿时长
4 weeks
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