LRCH1 deficiency enhances LAT signalosome formation and CD8(+) T cell responses against tumors and pathogens
LRCH1 deficiency enhances LAT signalosome formation and CD8(+) T cell responses against tumors and pathogens
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LRCH1 缺陷增强 LAT 信号体形成和 CD8( ) T 细胞对肿瘤和病原体的反应
DOI：
10.1073/pnas.2000970117
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发表时间：
2020
影响因子：
11.1
通讯作者：
Wang Hongyan
中科院分区：
文献类型：
--
作者：
Liu Chang;Xu Xiaoyan;Han Lei;Wan Xiaopeng;Zheng Lingming;Li Chunyang;Liao Zhaohui;Xiao Jun;Zhong Ruiyue;Zheng Xin;Wang Qiong;Li Zonghai;Chen Hualan;Wei Bin;Wang Hongyan
CD 8 +T细胞在消灭病原体和肿瘤细胞中起着关键作用。T细胞受体（TCR）信号传导对于CD 8 +T细胞的最佳活化至关重要。在TCR接合后，跨膜衔接蛋白LAT（用于活化T细胞的接头）募集其他关键信号传导分子并形成用于下游信号转导的“LAT信号体”。然而，很少有人知道哪些功能伴侣可以抑制LAT信号体的形成和抑制CD 8+细胞毒性T淋巴细胞（CTL）介导的细胞毒性。在这里，我们已经证明LRCH 1（富含亮氨酸的重复序列和钙调蛋白同源结构域包含1）直接结合LAT，减少LAT磷酸化和与GRB 2的相互作用，也促进LAT的内吞作用。LrCH 1 −/−小鼠表现出更好的抗流感病毒和李斯特菌感染的保护作用，具有增强的CD 8 +T细胞增殖和细胞毒性。Lrch 1 −/− CD 8 + CTL的连续转移导致体内B16-MO 5肿瘤清除率增加。此外，在识别肝肿瘤相关抗原磷脂酰肌醇蛋白聚糖-3的人嵌合抗原受体（CAR）T细胞中敲除LRCH 1可以改善CAR T细胞的体外迁移和增殖。这些发现表明LRCH 1是一个潜在的翻译靶点，可以改善针对感染和肿瘤的T细胞免疫疗法。
CD8+T cells play pivotal roles in eradicating pathogens and tumor cells. T cell receptor (TCR) signaling is vital for the optimal activation of CD8+T cells. Upon TCR engagement, the transmembrane adapter protein LAT (linker for activation of T cells) recruits other key signaling molecules and forms the “LAT signalosome” for downstream signal transduction. However, little is known about which functional partners could restrain the formation of the LAT signalosome and inhibit CD8+cytotoxic T lymphocyte (CTL)-mediated cytotoxicity. Here we have demonstrated that LRCH1 (leucine-rich repeats and calponin homology domain containing 1) directly binds LAT, reduces LAT phosphorylation and interaction with GRB2, and also promotes the endocytosis of LAT.Lrch1−/−mice display better protection against influenza virus andListeriainfection, with enhanced CD8+T cell proliferation and cytotoxicity. Adoptive transfer ofLrch1−/−CD8+CTLs leads to increased B16-MO5 tumor clearance in vivo. Furthermore, knockout ofLRCH1in human chimeric antigen receptor (CAR) T cells that recognize the liver tumor-associated antigen glypican-3 could improve CAR T cell migration and proliferation in vitro. These findings suggest LRCH1 as a potential translational target to improve T cell immunotherapy against infection and tumors.