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Bat3 promotes T cell responses and autoimmunity by repressing Tim-3mediated cell death and exhaustion

Rangachari, M;Zhu, C;Sakuishi, K;Xiao, S;Karman, J;Chen, A;Angin, M;Wakeham, A;Greenfield, EA;Sobel, RA;Okada, H;McKinnon, PJ;Mak, TW;Addo, MM;Anderson, AC;Kuchroo, VK;

T cell immunoglobulin and mucin domaincontaining 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-9mediated 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-antigenspecific CD4+ T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3hi, interferon- (IFN-)loCD4+ cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3+ T cells from mouse tumors and HIV-1infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers.