The TCR Cα Domain Regulates Responses to Self-pMHC Class II.
The TCR Cα Domain Regulates Responses to Self-pMHC Class II.
复制标题
DOI：
10.4049/jimmunol.2200377
复制
发表时间：
2022-11-15
期刊：
影响因子：
--
通讯作者：
Kuhns MS
中科院分区：
文献类型：
--
作者：
Kim CY;Parrish HL;Kuhns MS
T细胞通过其克隆型T细胞受体(TCR)识别MHC分子(PMHC)中的多肽抗原，在获得性免疫中发挥核心作用。αβα是由可变结构域(Vβ，Vα)和恒定结构域(Cβ，Cα)组成的异源二聚体。Vα、Vβ和Cβ结构域在细胞外空间采用典型的免疫球蛋白(Ig)折叠，而Cα结构域缺乏顶端β片层，而其表面有两条松散关联的顶链(C和F链)。先前的结果表明，这种独特的Ig样折叠介导了同型TCR相互作用，并影响了体外信号转导。为了更好地理解为什么进化选择了这种独特的结构，我们问：携带CαC链突变的小鼠cd4+T细胞的发育和功能的适合性成本是多少？在TCR逆转录和转基因小鼠中，我们观察到与表达野生型TCR的小鼠相比，携带突变TCR的单个阳性胸腺细胞增加。此外，我们对突变的TCR转基因小鼠的分析显示，与野生型相比，经历强紧张性TCR信号的幼稚CD4+T细胞增加，动态平衡存活率增加，应答分子招募到同源的pMHCII。然而，该突变并没有明显影响免疫后的CD4+T细胞的增殖或分化。我们将这些数据解释为独特的C-α结构域已经进化到微调TCRs信号，特别是在响应与自身pMHCII的弱相互作用时。
T-cells play a central role in adaptive immunity by recognizing peptide-antigens presented in MHC molecules (pMHC) via their clonotypic T-cell receptors (TCRs). αβTCRs are heterodimers, consisting of TCRα and TCRβ subunits that are composed of variable (Vα, Vβ) and constant (Cα, Cβ) domains. While the Vα, Vβ, and Cβ domains adopt typical immunoglobulin (Ig) folds in the extracellular space, the Cα domain lacks a top β sheet and instead has two loosely associated top strands (C and F strands) on its surface. Previous results suggest that this unique Ig-like fold mediates homotypic TCR interactions and influences signaling in vitro. To better understand why evolution has selected this unique structure, we asked: what is the fitness cost for development and function of mouse CD4+ T cells bearing a mutation in the Cα C-strand? In both TCR retrogenic and transgenic mice we observed increased single positive thymocytes bearing mutant TCRs compared with those expressing wild type TCRs. Furthermore, our analysis of mutant TCR transgenic mice revealed an increase in naive CD4+ T cells experiencing strong tonic TCR signals, increased homeostatic survival, and increased recruitment of responders to cognate pMHCII upon immunization compared to wild type. The mutation did not, however, overtly impact CD4+ T cell proliferation or differentiation after immunization. We interpret these data as evidence that the unique Cα domain has evolved to fine-tune TCR signaling, particularly in response to weak interactions with self-pMHCII.
影响因子：
7.3
作者：
Wang JH;Reinherz EL
通讯作者：
Reinherz EL