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

Nature Medicine volume 18, pages 1394–1400 (2012)Cite this article

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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.

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Figure 1: Bat3 binds to the Tim-3 tail in a galectin-9–dependent manner.
Figure 2: Bat3 promotes TH1 cell function and protects from galectin-9–mediated cell death.
Figure 3: Bat3 expression in the hematopoietic compartment promotes CNS autoimmunity.
Figure 4: Loss of Bat3 function in T cells induces an exhausted-like phenotype.
Figure 5: Bat3 expression in CD4+ T cells is required for TH1 cell–driven EAE.
Figure 6: Bat3 expression is reduced in Tim-3+ exhausted T cells.

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  • 21 August 2012

     In the version of this article initially published online, the x axis in Figure 6c was incorrectly labeled. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank D. Kozoriz, D. Lee, J. Sullivan and M. King for technical assistance; J. Zhang (Brigham and Women's Hospital, Boston) for reagents; B.H. Waksman for valuable guidance and discussion; and B. Walker for critical reading of the manuscript. M.R. was previously supported by Fellowships from the Multiple Sclerosis Society of Canada (MSSOC) and the Canadian Institutes of Health Research (CIHR) and is currently supported by the EMD Serono, Canada and an MS Research and Training Network Transitional Career Development Award from the MSSOC and the Multiple Sclerosis Scientific Research Foundation. K.S. holds a Fellowship from the Sankyo Foundation of Life Science. These studies were funded by grants from the US National Institutes of Health to V.K.K. (NS045937, AI073748 and NS038037) and S.X. (K01DK090105), the Ragon Institute of MGH, MIT and Harvard (V.K.K., C.Z. and M.M.A.), the American Cancer Society (A.C.A.) and the Harvard University Center for AIDS Research (M.M.A.; P30 AI060354).

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Author notes

  1. Jozsef Karman

    Present address: Present address: Genzyme Corp., Framingham, Massachusetts, USA.,

  2. Manu Rangachari and Chen Zhu: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

    Manu Rangachari, Chen Zhu, Kaori Sakuishi, Sheng Xiao, Jozsef Karman, Andrew Chen, Ana C Anderson & Vijay K Kuchroo

  2. Ragon Institute of MGH, MIT and Harvard, Charlestown, Massachusetts, USA

    Mathieu Angin & Marylyn M Addo

  3. Campbell Family Breast Cancer Research Institute, Princess Margaret Hospital, Toronto, Ontario, Canada

    Andrew Wakeham, Hitoshi Okada & Tak W Mak

  4. Dana Farber Cancer Institute, Boston, Massachusetts, USA

    Edward A Greenfield

  5. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

    Raymond A Sobel

  6. Division of Signaling Biology, Ontario Cancer Institute, Toronto, Ontario, Canada

    Hitoshi Okada

  7. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Hitoshi Okada

  8. St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Peter J McKinnon

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Contributions

M.R. and C.Z. designed and performed experiments, and collected data. M.R. wrote the manuscript. K.S., S.X., J.K., A.C. and M.A. provided help in performing experiments. A.W. helped generate fetal liver chimeric mice. E.A.G. helped generate Bat3 antiserum. R.A.S. analyzed histopathological data. H.O. generated the Bag6−/− strain. P.J.M. and T.W.M. provided Bag6+/− mice and fetal liver chimeras, respectively. M.M.A. and A.C.A. designed and supervised experiments involving HIV samples and tumor mice, respectively. V.K.K. supervised the project and edited the manuscript.

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Correspondence to Vijay K Kuchroo.

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Rangachari, M., Zhu, C., Sakuishi, K. et al. Bat3 promotes T cell responses and autoimmunity by repressing Tim-3–mediated cell death and exhaustion. Nat Med 18, 1394–1400 (2012). https://doi.org/10.1038/nm.2871

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