Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Nat Med. 2012 Sep;18(9):1394-400. doi: 10.1038/nm.2871.
T cell immunoglobulin and mucin domain–containing 3 (Tim-3) is an inhibitory receptor that is expressed on exhausted T cells during infection with HIV-1 and hepatitis C virus. By contrast, Tim-3 expression and function are defective in multiple human autoimmune diseases. However, the molecular mechanisms modulating Tim-3 function are not well understood. Here we show that human leukocyte antigen B (HLA-B)-associated transcript 3 (Bat3) binds to, and represses the function of, Tim-3. Bat3 protects T helper type 1 (TH1) cells from galectin-9–mediated cell death and promotes both proliferation and proinflammatory cytokine production. Bat3-deficient T cells have elevated expression of exhaustion-associated molecules such as Tim-3, Lag3, Prdm1 and Pbx3, and Bat3 knockdown in myelin-antigen–specific CD4+ T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3hi, interferon-γ (IFN-γ)loCD4+ cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3+ T cells from mouse tumors and HIV-1–infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3–dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers.
T 细胞免疫球蛋白和粘蛋白结构域 3（Tim-3）是一种抑制性受体，在感染 HIV-1 和丙型肝炎病毒时表达于耗尽的 T 细胞上。相比之下，Tim-3 的表达和功能在多种人类自身免疫性疾病中存在缺陷。然而，调节 Tim-3 功能的分子机制尚不清楚。在这里，我们表明人类白细胞抗原 B（HLA-B）相关转录物 3（Bat3）与 Tim-3 结合并抑制其功能。Bat3 可保护辅助性 T 细胞 1（TH1）细胞免受半乳糖凝集素-9 介导的细胞死亡，并促进增殖和促炎细胞因子的产生。Bat3 缺陷型 T 细胞高表达衰竭相关分子，如 Tim-3、Lag3、Prdm1 和 Pbx3，Bat3 在髓鞘抗原特异性 CD4+T 细胞中的敲低可显著抑制实验性自身免疫性脑脊髓炎的发展，同时促进功能失调的 Tim-3hi、干扰素-γ（IFN-γ）loCD4+细胞群的扩张。此外，在来自小鼠肿瘤和 HIV-1 感染个体的耗尽的 Tim-3+T 细胞中，Bat3 的表达减少。这些数据表明，Bat3 作为 Tim-3 依赖性衰竭和细胞死亡的抑制剂发挥作用。Bat3 因此可能成为自身免疫性疾病、慢性感染和癌症的可行治疗靶点。
