Self-programmed dynamics of T cell receptor condensation.
Self-programmed dynamics of T cell receptor condensation.
复制标题
T细胞受体冷凝的自编程动力学。
DOI：
10.1073/pnas.2217301120
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发表时间：
2023-07-11
影响因子：
11.1
通讯作者：
Lou, Jizhong
中科院分区：
文献类型：
--
作者：
Chen, Hui;Xu, Xinyi;Hu, Wei;Wu, Songfang;Xiao, Jianhui;Wu, Peng;Wang, Xiaowen;Han, Xuling;Zhang, Yanruo;Zhang, Yong;Jiang, Ning;Liu, Wanli;Lou, Changjie;Chen, Wei;Xu, Chenqi;Lou, Jizhong
关键词：
了解T细胞受体（TCR）信号不仅对揭示免疫机制很重要，而且对开发下一代免疫疗法也至关重要。我们发现CD3ε作为TCR的一个组分，可以通过离子相互作用本质上与Lck形成相分离。凝析结构显著促进lck介导的CD3磷酸化，从而产生TCR信号的扩增。作为一个自然的结果，磷酸化的CD3ε反过来招募一个高亲和力的竞争对手Csk，它可以溶解凝结物并直接抑制Lck活性，从而导致TCR信号的终止。这种组装或溶解缩合的自编程特征不仅解决了长期存在的动态TCR聚类问题，而且还突出了一种新的缩合模型，可能与许多其他受体系统相关。受体-配体结合的一个常见事件是在细胞表面形成受体簇，其中信号分子被特异性地招募或排除以形成信号中枢来调节细胞事件。这些集群通常是短暂的，可以拆卸以终止信令。尽管动态受体聚集在细胞信号传导中具有普遍的相关性，但这种动态的调控机制仍然知之甚少。作为免疫系统中主要的抗原受体，T细胞受体（TCR）形成时空动态簇，介导稳健而有时间性的信号传导，诱导适应性免疫反应。在这里，我们确定了一种控制动态TCR聚类和信号的相分离机制。TCR信号组分CD3ε链可以通过相分离与Lck激酶凝聚形成TCR信号体，用于活性抗原信号传导。然而，Lck介导的CD3ε磷酸化将其结合偏好转换为Lck的功能性抑制因子Csk，从而导致TCR信号体的溶解。通过靶向CD3ε与Lck或Csk的相互作用来调节TCR/Lck缩合，直接影响T细胞的活化和功能，凸显了相分离机制的重要性。因此，自编程的冷凝和溶解是TCR信号传导的内在机制，可能与其他受体有关。
Understanding T cell receptors (TCR) signaling is not only important for unraveling the mechanisms of immunity but also crucial for developing next-generation immunotherapy. We find that CD3ε, a component of TCR, can intrinsically form phase separation with Lck through ionic interactions. The condensate structure significantly promotes Lck-mediated CD3 phosphorylation to yield the amplification of TCR signaling. As a natural consequence, phosphorylated CD3ε in turn recruits a high-affinity competitor Csk that can dissolve the condensate and directly inhibit Lck activity, which leads to the termination of TCR signaling. This self-programmed feature of assembling or dissolvement of condensation not only solves a long-standing question of dynamic TCR clustering but also highlights a new model of condensation that could be relevant to many other receptor systems. A common event upon receptor–ligand engagement is the formation of receptor clusters on the cell surface, in which signaling molecules are specifically recruited or excluded to form signaling hubs to regulate cellular events. These clusters are often transient and can be disassembled to terminate signaling. Despite the general relevance of dynamic receptor clustering in cell signaling, the regulatory mechanism underlying the dynamics is still poorly understood. As a major antigen receptor in the immune system, T cell receptors (TCR) form spatiotemporally dynamic clusters to mediate robust yet temporal signaling to induce adaptive immune responses. Here we identify a phase separation mechanism controlling dynamic TCR clustering and signaling. The TCR signaling component CD3ε chain can condensate with Lck kinase through phase separation to form TCR signalosomes for active antigen signaling. Lck-mediated CD3ε phosphorylation, however, switched its binding preference to Csk, a functional suppressor of Lck, to cause the dissolvement of TCR signalosomes. Modulating TCR/Lck condensation by targeting CD3ε interactions with Lck or Csk directly affects T cell activation and function, highlighting the importance of the phase separation mechanism. The self-programmed condensation and dissolvement is thus a built-in mechanism of TCR signaling and might be relevant to other receptors.
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影响因子：
30.5
作者：
Chang VT;Fernandes RA;Ganzinger KA;Lee SF;Siebold C;McColl J;Jönsson P;Palayret M;Harlos K;Coles CH;Jones EY;Lui Y;Huang E;Gilbert RJC;Klenerman D;Aricescu AR;Davis SJ
通讯作者：
Davis SJ
影响因子：
16.8
作者：
Hui E;Vale RD
通讯作者：
Vale RD
影响因子：
56.9
作者：
Lee, KH;Holdorf, AD;Shaw, AS
通讯作者：
Shaw, AS
影响因子：
64.8
作者：
Li, Pilong;Banjade, Sudeep;Cheng, Hui-Chun;Kim, Soyeon;Chen, Baoyu;Guo, Liang;Llaguno, Marc;Hollingsworth, Javoris V.;King, David S.;Banani, Salman F.;Russo, Paul S.;Jiang, Qiu-Xing;Nixon, B. Tracy;Rosen, Michael K.
通讯作者：
Rosen, Michael K.
影响因子：
30.5
作者：
Demetriou P;Abu-Shah E;Valvo S;McCuaig S;Mayya V;Kvalvaag A;Starkey T;Korobchevskaya K;Lee LYW;Friedrich M;Mann E;Kutuzov MA;Morotti M;Wietek N;Rada H;Yusuf S;Afrose J;Siokis A;Oxford IBD Cohort Investigators;Meyer-Hermann M;Ahmed AA;Depoil D;Dustin ML
通讯作者：
Dustin ML