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 and Listeria infection, with enhanced CD8⁺ T cell proliferation and cytotoxicity. Adoptive transfer of Lrch1^−/− CD8⁺ CTLs leads to increased B16-MO5 tumor clearance in vivo. Furthermore, knockout of LRCH1 in 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.

CD8 ⁺ T细胞在根除病原体和肿瘤细胞方面起着关键作用。T细胞受体（TCR）信号对于CD8 ⁺ T细胞的最佳激活至关重要。在TCR参与后，跨膜衔接蛋白LAT（用于激活T细胞的连接子）募集其他关键信号分子，并形成“ LAT信号体”用于下游信号转导。然而，鲜为人知的是哪个功能伙伴可以抑制LAT信号体的形成并抑制CD8 ⁺细胞毒性T淋巴细胞（CTL）介导的细胞毒性。在这里，我们已经证明了LRCH1（富含亮氨酸的重复序列和包含1的钙还原蛋白同源结构域）直接结合LAT，减少LAT磷酸化和与GRB2的相互作用，还促进LAT的内吞作用。Lrch1 ^-/-小鼠显示出更好的针对流感病毒和李斯特菌感染的保护作用，并具有增强的CD8 ⁺ T细胞增殖和细胞毒性作用。Lrch1 ^-/- CD8 ⁺ CTL的过继转移导致体内B16-MO5肿瘤清除率增加。此外，在人类嵌合抗原受体（CAR）T细胞中敲除LRCH1，可以识别肝肿瘤相关抗原glypican-3，可以改善CAR T细胞在体外的迁移和增殖。这些发现表明，LRCH1是潜在的翻译靶标，可改善针对感染和肿瘤的T细胞免疫疗法。