Bat3 Protects T cell Responses by Repressing Tim-3-Mediated Exhaustion and Death

Interferon (IFN)γ-secreting Th1 CD4+ cells and Tc1 CD8+ cells play an essential role in protection against intracellular pathogens and viruses, and IFNγ production from lymphocytes is a critical component of tumor immunosurveillance1 and resistance to chronic viral infections2,3. Exacerbated Th1 responses to self-antigens are, however, implicated in murine and human autoimmune diseases3,4. Thus, IFNγ-producing T cells both induce human autoimmune diseases as well as protect against chronic viral infections and cancers. T cell immunoglobulin and mucin domain-containing-3 (Tim-3) is an inhibitory receptor specifically expressed on terminally differentiated Th1 and Tc1 cells5. Tim-3 is critical for the induction of T cell tolerance in vivo6,7, and defective Tim-3 expression and signaling have been observed in CD4+ T cells isolated from MS8,9 and colitis10 patients. Furthermore, provocative recent findings show that Tim-3 plays a critical role in the development of T cell exhaustion in chronic viral infections such as HIV11, HCV12, LCMV13 and Friend virus14 as well as in tumor-bearing individuals15–17. The interaction of Tim-3 with its ligand galectin-9 triggers cell death and in vivo blockade of galectin-9 substantially enhances the severity of murine experimental autoimmune encephalomyelitis (EAE)18. The galectin-9/Tim-3 axis is thus an important negative regulator of Th1 and Tc1 cell function that could be exploited therapeutically. While boosting Tim-3 signals could dampen autoimmunity, repressing Tim-3 function could augment immune responses to viral infections and cancers. Developing such strategies requires greater insight into the molecular mechanisms of Tim-3-mediated T cell regulation. Here we identify HLA-B-associated transcript 3 (Bat3) as a binding partner to the Tim-3 intracellular tail. Bat3 protects Th1 cells from galectin-9 mediated cell death, and promotes both proliferation and pro-inflammatory cytokine production. In contrast, knockdown of Bat3 in myelin antigen-specific Th1 cells ablates their function and pathogenicity, and promotes T cell exhaustion in vivo. Further, Bat3 expression is specifically reduced in exhausted Tim-3+ CD4+ T cells isolated from murine tumors and also from HIV-1-infected individuals. Bat3 may thus represent an important novel repressor of Tim-3 signaling that protects Th1 responses from Tim-3-mediated inhibition.