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Tim-3 inhibits T helper type 1–mediated auto- and alloimmune responses and promotes immunological tolerance

Nature Immunology volume 4, pages 1093–1101 (2003)Cite this article

Abstract

Although T helper (TH) cell–mediated immunity is required to effectively eliminate pathogens, unrestrained TH activity also contributes to tissue injury in many inflammatory and autoimmune diseases. We report here that the TH type 1 (TH1)-specific Tim-3 (T cell immunoglobulin domain, mucin domain) protein functions to inhibit aggressive TH1-mediated auto- and alloimmune responses. Tim-3 pathway blockade accelerated diabetes in nonobese diabetic mice and prevented acquisition of transplantation tolerance induced by costimulation blockade. These effects were mediated, at least in part, by dampening of the antigen-specific immunosuppressive function of CD4+CD25+ regulatory T cell populations. Our data indicate that the Tim-3 pathway provides an important mechanism to down-regulate TH1-dependent immune responses and to facilitate the development of immunological tolerance.

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Figure 1: Expression of Tim-3 and Tim-3L.
Figure 2: Treatment with both Tim-3 mAb and flTim-3–Ig augments autoimmune diabetes in an adoptive transfer NOD model.
Figure 3: Generation of Tim-3-deficient mice.
Figure 4: Tim-3 contributes to the tolerizing effects of treatment with DST plus anti-CD154 in an MHC-mismatched islet allograft model.
Figure 5: Tim-3 modulates the alloantigen-specific effects of treatment with DST plus anti-CD154 on CD4+CD25+ regulatory T cells.

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Acknowledgements

We thank Chimerigen (Allston, Massachusetts) for providing purified fusion proteins, and Y. Tian for technical assistance. Supported by the Juvenile Diabetes Research Foundation (X.X.Z. and A.S.-F.), the National Institute of Allergy and Infectious Diseases (T.B.S.) and the Juvenile Diabetes Research Foundation Center for Islet Transplantation at Harvard Medical School (T.B.S.).

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Authors and Affiliations

  1. Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Alberto Sánchez-Fueyo, Christoph Domenig, Xin Xiao Zheng & Terry B Strom

  2. Inflammation Department, Experimental Medicine Division, Millennium Pharmaceuticals, Cambridge, 02116, Massachusetts, USA

    Jane Tian, Dominic Picarella, José-Carlos Gutiérrez-Ramos & Anthony J Coyle

  3. Brigham and Women's Hospital, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Catherine A Sabatos & Vijay K Kuchroo

  4. Department of Haematology, Division of Investigative Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Natasha Manlongat

  5. Deutsches Rheumaforschungs Zentrum, Berlin, D-10117, Germany

    Orissa Bender & Thomas Kamradt

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Correspondence to Anthony J Coyle or Terry B Strom.

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Competing interests

J.T., D.P., J.-C.G.-R. and A.J.C. are employed by Millennium Pharmaceuticals, which holds the patent on Tim-3, as does V.K.K.

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Sánchez-Fueyo, A., Tian, J., Picarella, D. et al. Tim-3 inhibits T helper type 1–mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol 4, 1093–1101 (2003). https://doi.org/10.1038/ni987

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