A single-amino acid substitution in the adaptor LAT accelerates TCR proofreading kinetics and alters T-cell selection, maintenance and function.
A single-amino acid substitution in the adaptor LAT accelerates TCR proofreading kinetics and alters T-cell selection, maintenance and function.
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DOI：
10.1038/s41590-023-01444-x
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发表时间：
2023-04
影响因子：
30.5
通讯作者：
Weiss, Arthur
中科院分区：
文献类型：
--
作者：
Lo, Wan-Lin;Kuhlmann, Miriam;Rizzuto, Gabrielle;Ekiz, H. Atakan;Kolawole, Elizabeth M.;Revelo, Monica P.;Andargachew, Rakieb;Li, Zhongmei;Tsai, Yuan-Li;Marson, Alexander;Evavold, Brian D.;Zehn, Dietmar;Weiss, Arthur
成熟的T细胞必须区分与自身肽的短暂相互作用和与激动剂的长期结合。动力学校正模型假定某些T细胞抗原受体信号传导节点充当分子计时器以促进这种区分。然而，这种调节机制的生理意义和破坏它的病理后果是未知的。在这里，我们报告说，加速正常缓慢的磷酸化的接头激活T细胞（LAT）残基Y136通过引入相邻的Gly135Asp改变（LATG135D）破坏配体歧视在体内。LATG 135D T细胞的增强的自身反应性触发过度的胸腺负选择并促进T细胞无反应性。在李斯特菌感染期间，LATG135D T细胞响应于非常弱的刺激而比野生型对应物扩增更多，但显示效应器和记忆反应之间的不平衡。此外，尽管它们增强了中枢和外周耐受机制的参与，但携带LATG 135D的小鼠显示出与自身免疫和免疫病理学相关的特征。我们的数据揭示了动力学校正在平衡耐受性和免疫力方面的重要性。Lo及其同事通过LAT Gly135Asp改变为TCR动力学校正模型提供了证据，以揭示胸腺选择和成熟T细胞应答中TCR活化动力学改变的功能后果。
Mature T cells must discriminate between brief interactions with self-peptides and prolonged binding to agonists. The kinetic proofreading model posits that certain T-cell antigen receptor signaling nodes serve as molecular timers to facilitate such discrimination. However, the physiological significance of this regulatory mechanism and the pathological consequences of disrupting it are unknown. Here we report that accelerating the normally slow phosphorylation of the linker for activation of T cells (LAT) residue Y136 by introducing an adjacent Gly135Asp alteration (LATG135D) disrupts ligand discrimination in vivo. The enhanced self-reactivity of LATG135D T cells triggers excessive thymic negative selection and promotes T-cell anergy. During Listeria infection, LATG135D T cells expand more than wild-type counterparts in response to very weak stimuli but display an imbalance between effector and memory responses. Moreover, despite their enhanced engagement of central and peripheral tolerance mechanisms, mice bearing LATG135D show features associated with autoimmunity and immunopathology. Our data reveal the importance of kinetic proofreading in balancing tolerance and immunity. Lo and colleagues provide evidence for the TCR kinetic proofreading model by LAT Gly135Asp alteration to reveal functional consequences of altered kinetics in TCR activation in thymic selection and mature T-cell responses.
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DOI：
10.1073/pnas.2008303117
发表时间：
2020-10-20
影响因子：
11.1
作者：
Ganti, Raman S.;Lo, Wan-Lin;Chakraborty, Arup K.
通讯作者：
Chakraborty, Arup K.
影响因子：
7.2
作者：
Balagopalan, Lakshmi;Coussens, Nathan P.;Sommers, Connie L.
通讯作者：
Sommers, Connie L.
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
8.8
作者：
Jennings E;Elliot TAE;Thawait N;Kanabar S;Yam-Puc JC;Ono M;Toellner KM;Wraith DC;Anderson G;Bending D
通讯作者：
Bending D
DOI：
10.1073/pnas.92.11.5042
发表时间：
1995-05-23
影响因子：
11.1
作者：
MCKEITHAN, TW
通讯作者：
MCKEITHAN, TW