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.
Highlights d The susceptibility of CD4 + T cell subsets to HIV-1 matches their metabolic activity d HIV-1 selectively infects CD4 + T cells with enhanced glycolysis and OXPHOS d Inhibition of metabolic activities blocks HIV-1 replication d Suboptimal inhibition of glycolysis impairs amplification of HIV-1 reservoirs
Nature MetabolisM T cells ex vivo can be isolated from HICs but not from cART individuals 8,10,18 (Fig. 1a). In the present study, it was first investigated whether this capacity of HIC CD8 + T cells could be found among naive, central memory, transitional memory and effector memory CD8 + T cell subsets (see Supplementary Fig. 1). As expected, naive CD8 + T cells from HICs had no HIV-suppressive capacity. In contrast, all sorted memory CD8 + T cell subsets from HICs, but not from cART individuals, suppressed HIV infection as efficiently as bulk CD8 + T cells (Fig. 1b). Therefore, although effector memory cells probably had more immediate antiviral capacity 12 , HIVspecific CD8 + TCMs from HICs can efficiently react to counteract HIV-1 infection during co-culture. These results support the view that the strong antiviral potential of HICs is already embedded in the programme of their HIV-specific CD8 + TCMs. Distinct gene expression profile in HIV-specific CD8 + TCMs from HICs. A comparison was then made of the single-cell gene expression profiles (96 genes associated with CD8 + T cell function, differentiation, metabolism and survival (see Supplementary Fig. 2 and Supplementary Data 1) of HIV-specific CD8 + TCMs from five HICs whose CD8 + T cells had strong HIV-suppressive capacity and from five cART individuals (see Supplementary Table 1). Cells from cART individuals and HICs analysed in the present study shared not only the same differentiation status but also the same activation phenotype, as defined by flow cytometry (Fig. 1c and see Supplementary Table 2). Despite their similar phenotype, t-SNE (t-distributed stochastic neighbour-embedding algorithm)-based
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