LAG-3 inhibits the activation of CD4+ T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII
LAG-3 inhibits the activation of CD4+ T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII
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DOI：
10.1038/s41590-018-0217-9
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发表时间：
2018-12-01
影响因子：
30.5
通讯作者：
Okazaki, Taku
中科院分区：
文献类型：
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作者：
Maruhashi, Takumi;Okazaki, Il-Mi;Okazaki, Taku
靶向抑制性共受体PD-1和CTLA-4的肿瘤免疫治疗的成功表明，许多其他共受体可能是潜在的可药物化靶点，尽管关于它们的功能差异的信息有限。在这里，我们确定了一个独特的目标选择性的抑制性共受体LAG-3是固有的免疫调节作用。虽然LAG-3已被报道识别主要组织相容性复合体（MHC）II类，但它并不普遍识别MHC II类;相反，我们发现它选择性地识别肽和MHC II类（pMHCII）的稳定复合物。LAG-3不直接干扰辅助受体CD 4和MHC II类之间或T细胞抗原受体和MHC II类之间的相互作用。相反，LAG-3通过其细胞内区域转导抑制信号优先抑制对稳定pMHCII应答的T细胞。因此，LAG-3可能比以前认为的更具选择性，从而保持对显性自身抗原的耐受性。
The success of tumor immunotherapy targeting the inhibitory co-receptors PD-1 and CTLA-4 has indicated that many other co-receptors might be potential druggable targets, despite limited information about their functional differences. Here we identified a unique target selectivity for the inhibitory co-receptor LAG-3 that was intrinsic to its immunoregulatory roles. Although LAG-3 has been reported to recognize major histocompatibility complex (MHC) class II, it did not recognize MHC class II universally; instead, we found that it selectively recognized stable complexes of peptide and MHC class II (pMHCII). LAG-3 did not directly interfere with interactions between the co-receptor CD4 and MHC class II or between the T cell antigen receptor and MHC class II. Instead, LAG-3 preferentially suppressed T cells responsive to stable pMHCII by transducing inhibitory signals via its intracellular region. Thus, LAG-3 might function more selectively than previously thought and thereby maintain tolerance to dominant autoantigens.