Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion.
Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion.
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DOI：
10.1038/nm.2871
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发表时间：
2012-09
期刊：
影响因子：
82.9
通讯作者：
Kuchroo, Vijay K.
中科院分区：
文献类型：
--
作者：
Rangachari, Manu;Zhu, Chen;Sakuishi, Kaori;Xiao, Sheng;Karman, Jozsef;Chen, Andrew;Angin, Mathieu;Wakeham, Andrew;Greenfield, Edward A.;Sobel, Raymond A.;Okada, Hitoshi;McKinnon, Peter J.;Mak, Tak W.;Addo, Marylyn M.;Anderson, Ana C.;Kuchroo, Vijay K.
T细胞免疫球蛋白和含粘蛋白结构域3（Tim-3）是在HIV-1和HCV感染期间在耗尽的T细胞上表达的抑制性受体。相反，Tim-3的表达和功能在多种人类自身免疫性疾病中是有缺陷的。然而，Tim-3功能的分子机制仍然知之甚少。在这里，我们表明HLA-B相关转录本3（Bat 3）结合并抑制Tim-3的功能。Bat 3缺陷型T细胞显示耗竭标志物的表达升高，并且敲低髓鞘抗原特异性CD 4 + T细胞中的Bat 3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-3 hiIFN γlo CD 4+细胞群的扩增。此外，来自鼠肿瘤和HIV-1感染个体的耗尽的Tim-3+ T细胞显示出显著降低的Bat 3表达，并且Bat 3的靶向缺失诱导T细胞中的耗尽表型。这些数据表明，Bat 3作为抑制Tim-3依赖性细胞死亡/耗竭的分子安全捕获物，表明Bat 3可能代表自身免疫性疾病、慢性感染和癌症中的可行治疗靶标。
T cell immunoglobulin and mucin domain-containing-3 (Tim-3) is an inhibitory receptor expressed on exhausted T cells during HIV-1 and HCV infection. By contrast, Tim-3 expression and function are defective in multiple human autoimmune diseases. However, the molecular mechanisms governing Tim-3 function remain poorly understood. Here we show that HLA-B-associated transcript 3 (Bat3) binds to, and represses the function of Tim-3. Bat3-deficient T cells display elevated expression of exhaustion markers, and knocking down Bat3 in myelin antigen-specific CD4+ T cells dramatically inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3hiIFNγlo CD4+ cell population. Furthermore, exhausted Tim-3+ T cells from murine tumors and HIV-1-infected individuals display substantially reduced Bat3 expression and targeted deletion of Bat3 induces an exhausted phenotype in T cells. These data indicate that Bat3 acts as a molecular safety catch that inhibits Tim-3-dependent cell death/exhaustion, suggesting that Bat3 may represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers.
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影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
DOI：
10.1084/jem.20060210
发表时间：
2006-06-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Koguchi K;Anderson DE;Yang L;O'Connor KC;Kuchroo VK;Hafler DA
通讯作者：
Hafler DA
影响因子：
4.8
作者：
Kwak, Joon Hyeok;Kim, Sung Il;Choi, Mary E.
通讯作者：
Choi, Mary E.
影响因子：
15.9
作者：
Blackburn, Shawn D.;Wherry, E. John
通讯作者：
Wherry, E. John
影响因子：
30.5
作者：
Blackburn, Shawn D.;Shin, Haina;Haining, W. Nicholas;Zou, Tao;Workman, Creg J.;Polley, Antonio;Betts, Michael R.;Freeman, Gordon J.;Vignali, Dario A. A.;Wherry, E. John
通讯作者：
Wherry, E. John