LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model.
LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model.
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LAG3和PD1共同抑制分子合作，以限制鼠卵巢癌模型中的CD8+ T细胞信号传导和抑制抗肿瘤免疫。
DOI：
10.18632/oncotarget.4751
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发表时间：
2015-09-29
期刊：
影响因子：
--
通讯作者：
Odunsi K
中科院分区：
文献类型：
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作者：
Huang RY;Eppolito C;Lele S;Shrikant P;Matsuzaki J;Odunsi K
免疫共抑制受体淋巴细胞激活基因3(LAG3)和程序性细胞死亡1(PD1)在自身免疫和肿瘤逃逸中起协同作用。在这里，我们展示了它们如何协作和相互作用来调节T细胞功能。我们首次发现LAG3和PD1在浸润性小鼠卵巢肿瘤的OVA特异性和非特异性T细胞上共表达。LAG3和PD1的双抗体阻断或基因敲除显著增强T效应功能，延缓肿瘤生长。LAG3和PD1共同定位于体外激活的CD8+T细胞的跨高尔基体小泡、早期/再循环内小体隔室、溶酶体和微管组织中心。重要的是，LAG3和PD1与PLCK聚集在免疫突触上。T细胞提取物的相互免疫沉淀表明LAG3和PD1之间存在物理相互作用。突变分析表明，LAG3的胞质结构域并不是与PD1结合所必需的，而PD1的ITIM和ITSM是其与LAG3结合所必需的。最后，LAG3蛋白还与已知在T细胞信号转导过程中被PD1招募的含有Src-Homology-2结构域的磷酸酶(SHP1/2)有关。我们的数据表明，LAG3与PD1的结合有助于它们快速运输到免疫突触，导致对T细胞信号的协同抑制作用。
The immune co-inhibitory receptors lymphocyte activation gene-3 (LAG3) and programmed cell death 1 (PD1) synergistically contribute to autoimmunity and tumor evasion. Here we demonstrate how they collaborate and interact to regulate T cell function. We first show that LAG3 and PD1 are co-expressed on both OVA-specific and non-specific T cells infiltrating murine ovarian tumors. Dual antibody blockade or genetic knockout of LAG3 and PD1 significantly enhanced T effector function and delayed tumor growth. LAG3 and PD1 co-localized in activated CD8+ T cells in vitro at the trans-Golgi vesicles, early/recycling endosomal compartments, lysosomes, and microtubule organizing center. Importantly, LAG3 and PD1 cluster with pLck at the immunological synapse. Reciprocal immunoprecipitation of T cell extracts revealed physical interaction between LAG3 and PD1. Mutational analyses indicate that the cytoplasmic domain of LAG3 is not absolutely required for its association with PD1, while the ITIM and ITSM of PD1 are necessary for its association with LAG3. Finally, LAG3 protein also associates with the Src-homology-2 domain-containing phosphatases (SHP1/2) which are known to be recruited by PD1 during T cell signaling. Our data indicate that the association of LAG3 with PD1 contributes to their rapid trafficking to the immunological synapse, leading to a synergistic inhibitory effect on T cell signaling.