Strong Basal/Tonic TCR Signals Are Associated with Negative Regulation of Naive CD4+ T Cells

Q3 Medicine
Wendy M. Zinzow-Kramer, E. Kolawole, J. Eggert, B. Evavold, Christopher D. Scharer, Byron B. Au-Yeung
{"title":"Strong Basal/Tonic TCR Signals Are Associated with Negative Regulation of Naive CD4+ T Cells","authors":"Wendy M. Zinzow-Kramer, E. Kolawole, J. Eggert, B. Evavold, Christopher D. Scharer, Byron B. Au-Yeung","doi":"10.1101/2022.04.20.488956","DOIUrl":null,"url":null,"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+ 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.","PeriodicalId":94037,"journal":{"name":"ImmunoHorizons","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2022-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"5","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"ImmunoHorizons","FirstCategoryId":"0","ListUrlMain":"https://doi.org/10.1101/2022.04.20.488956","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 5

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+ 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.
强基础/强直TCR信号与初始CD4+ T细胞负调控相关
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。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
3.70
自引率
0.00%
发文量
0
审稿时长
4 weeks
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信