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

Abstract

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.

Tim-3: An Emerging Target in the Cancer Immunotherapy Landscape

“…Investigators from a recent study reported that human leukocyte antigen B-associated transcript 3 (Bat3) binds to the cytoplasmic tail of Tim-3. Galectin-9-induced phosphorylation of the Tim-3 cytoplasmic tail triggers the release of Bat3, resulting in the accumulation of the catalytically inactive form of the lymphocyte-specific protein tyrosine kinase (Lck) and defective IL-2 and IFN-g production (25). These data suggest that Bat3 acts as a negative regulator of the inhibitory function of Tim-3.…”

“…1A and B). Indeed, Tim-3/PD-1 pathway coblockade is more effective than either Tim-3 or PD-1 pathway blockade alone at restoring tumor antigen-specific IFN-g production in CD8 þ T cells from tumor-bearing mice (25). Moreover, Tim-3/PD-1 pathway coblockade also drives the downmodulation of several genes associated with potent Tregsuppressor function in Tim-3 þ Tregs (21).…”

Glycobiology of cell death: when glycans and lectins govern cell fate

“…62 Recent studies implicated the human leukocyte antigen B-associated transcript (Bat3) as a molecular adaptor linked to the intracellular tail of TIM-3, which protects Th1 cells from galectin-9-induced apoptosis. 63 However, studies on TIM-3-galectin-9 interactions were so far based on exposure to exogenous galectin-9. Whether an additional ligand competes with galectin-9 for TIM-3 is less clear.…”

Bag6 complex contains a minimal tail-anchor–targeting module and a mock BAG domain

“…The genomic localization suggested a role in immune response, and this suggestion has been supported by evidence of its roles in Th1 cell survival (9), natural killer cell cytotoxicity (10), and MHC class II molecule presentation (11,12). The initial Bag6 link to apoptosis was based on its interaction with Reaper, an apoptosis-inducing Drosophila protein (13).…”