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

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    • Source:
      Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE
    • Publication Information:
      Publication: New York Ny : Nature Publishing Company
      Original Publication: New York, NY : Nature Pub. Co., [1995-
    • Subject Terms:
    • Abstract:
      T cell immunoglobulin and mucin domain–containing 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-9–mediated 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-antigen–specific CD4+ T cells markedly inhibits the development of experimental autoimmune encephalomyelitis while promoting the expansion of a dysfunctional Tim-3hi, interferon-γ (IFN-γ)loCD4+ cell population. Furthermore, expression of Bat3 is reduced in exhausted Tim-3+ T cells from mouse tumors and HIV-1–infected individuals. These data indicate that Bat3 acts as an inhibitor of Tim-3–dependent exhaustion and cell death. Bat3 may thus represent a viable therapeutic target in autoimmune disorders, chronic infections and cancers.
    • Comments:
      Comment in: Nat Med. 2012 Sep;18(9):1338-9. (PMID: 22961161)
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    • Grant Information:
      R01 NS045937 United States NS NINDS NIH HHS; K01 DK090105 United States DK NIDDK NIH HHS; K01DK090105 United States DK NIDDK NIH HHS; NS038037 United States NS NINDS NIH HHS; AI073748 United States AI NIAID NIH HHS; NS045937 United States NS NINDS NIH HHS; P01 AI073748 United States AI NIAID NIH HHS; P30 AI060354 United States AI NIAID NIH HHS; P01 NS038037 United States NS NINDS NIH HHS; R01 NS030843 United States NS NINDS NIH HHS; K08 AI074405 United States AI NIAID NIH HHS; R01 NS037956 United States NS NINDS NIH HHS; Canada CAPMC CIHR
    • Accession Number:
      0 (BAG6 protein, human)
      0 (BCL2-associated athanogene 1 protein)
      0 (DNA-Binding Proteins)
      0 (HAVCR2 protein, human)
      0 (Hepatitis A Virus Cellular Receptor 2)
      0 (Homeodomain Proteins)
      0 (Membrane Proteins)
      0 (Molecular Chaperones)
      0 (Transcription Factors)
      128559-51-3 (RAG-1 protein)
    • Publication Date:
      Date Created: 20120807 Date Completed: 20121113 Latest Revision: 20220331
    • Publication Date:
      20240829
    • Accession Number:
      PMC3491118
    • Accession Number:
      10.1038/nm.2871
    • Accession Number:
      22863785