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

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.

Pubmed ID: 22863785

Authors

  • 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

Journal

Nature medicine

Publication Data

September 5, 2012

Associated Grants

  • Agency: NIAID NIH HHS, Id: AI073748
  • Agency: NIDDK NIH HHS, Id: K01 DK090105
  • Agency: NIDDK NIH HHS, Id: K01DK090105
  • Agency: NIAID NIH HHS, Id: K08 AI074405
  • Agency: NINDS NIH HHS, Id: NS038037
  • Agency: NINDS NIH HHS, Id: NS045937
  • Agency: NIAID NIH HHS, Id: P01 AI073748
  • Agency: NINDS NIH HHS, Id: P01 NS038037
  • Agency: NIAID NIH HHS, Id: P30 AI060354
  • Agency: NIAID NIH HHS, Id: P30 AI060354
  • Agency: NINDS NIH HHS, Id: R01 NS030843
  • Agency: NINDS NIH HHS, Id: R01 NS037956
  • Agency: NINDS NIH HHS, Id: R01 NS045937
  • Agency: Canadian Institutes of Health Research, Id:

Mesh Terms

  • Animals
  • Autoimmunity
  • Cell Death
  • DNA-Binding Proteins
  • Flow Cytometry
  • Genetic Vectors
  • HEK293 Cells
  • Homeodomain Proteins
  • Humans
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Molecular Chaperones
  • Real-Time Polymerase Chain Reaction
  • Retroviridae
  • Statistics, Nonparametric
  • T-Lymphocytes
  • Transcription Factors
  • Transduction, Genetic