LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation.
LAG3 associates with TCR-CD3 complexes and suppresses signaling by driving co-receptor-Lck dissociation.
复制标题
LAG3与TCR-CD3复合物相关，并通过驱动共受体LCK解离来抑制信号传导。
DOI：
10.1038/s41590-022-01176-4
复制
发表时间：
2022-05
影响因子：
30.5
通讯作者：
Vignali, Dario A. A.
中科院分区：
文献类型：
--
作者：
Guy, Clifford;Mitrea, Diana M.;Chou, Po-Chien;Temirov, Jamshid;Vignali, Kate M.;Liu, Xueyan;Zhang, Hui;Kriwacki, Richard;Bruchez, Marcel P.;Watkins, Simon C.;Workman, Creg J.;Vignali, Dario A. A.
LAG 3是一种抑制性受体，在耗竭的T细胞上高度表达。尽管LAG 3靶向免疫治疗药物目前正在临床试验中，但LAG 3如何抑制T细胞功能仍不清楚。在这里，我们表明，LAG 3移动到免疫突触，并与T细胞受体（TCR）-CD 3复合物在CD 4+和CD 8 + T细胞，在没有结合到MHC II类，其典型的配体。从机制上讲，LAG 3胞质尾中遗传学保守的酸性串联谷氨酸-脯氨酸重复序列降低了免疫突触处的pH值，并导致酪氨酸激酶Lck从CD 4或CD 8共受体解离，这导致共受体-TCR信号传导的丧失和有限的T细胞活化。这些观察结果表明，LAG 3以MHC II类非依赖性方式作为信号干扰物发挥作用，并提供了对LAG 3靶向免疫疗法作用机制的深入了解。
LAG3 is an inhibitory receptor that is highly expressed on exhausted T cells. Although LAG3-targeting immunotherapeutics are currently in clinical trials, how LAG3 inhibits T cell function remains unclear. Here we show that LAG3 moved to the immunological synapse and associated with the T cell receptor (TCR)-CD3 complex in CD4+ and CD8+ T cells, In the absence of binding to MHC class II, its canonical ligand. Mechanistically, a phylogenetically conserved, acidic, tandem glutamic acid–proline repeat in the LAG3 cytoplasmic tail lowered the pH at the immune synapse and caused the dissociation of the tyrosine kinase Lck from the CD4 or CD8 co-receptor, which resulted in a loss of co-receptor-TCR signaling and limited T cell activation. These observations indicated that LAG3 functioned as a signal disruptor in an MHC class II-independent manner, and provide insight into the mechanism of action of LAG3-targeting immunotherapies.
登录
查看更多内容
DOI：
10.1084/jem.176.2.327
发表时间：
1992-08-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Baixeras E;Huard B;Miossec C;Jitsukawa S;Martin M;Hercend T;Auffray C;Triebel F;Piatier-Tonneau D
通讯作者：
Piatier-Tonneau D
影响因子：
64.8
作者：
Fu G;Guy CS;Chapman NM;Palacios G;Wei J;Zhou P;Long L;Wang YD;Qian C;Dhungana Y;Huang H;Kc A;Shi H;Rankin S;Brown SA;Johnson A;Wakefield R;Robinson CG;Liu X;Sheyn A;Yu J;Jackowski S;Chi H
通讯作者：
Chi H
影响因子：
56.9
作者：
Bates, Mark;Huang, Bo;Zhuang, Xiaowei
通讯作者：
Zhuang, Xiaowei
影响因子：
3.3
作者：
Johnson, AO;Lampson, MA;McGraw, TE
通讯作者：
McGraw, TE
影响因子：
30.5
作者：
Blackburn, Shawn D.;Shin, Haina;Haining, W. Nicholas;Zou, Tao;Workman, Creg J.;Polley, Antonio;Betts, Michael R.;Freeman, Gordon J.;Vignali, Dario A. A.;Wherry, E. John
通讯作者：
Wherry, E. John