Nature Immunology4, 1093 - 1101 (2003)
Published online: 12 October 2003; | doi:10.1038/ni987
Tim-3 inhibits T helper type 1−mediated auto- and alloimmune responses and promotes immunological tolerance
Alberto Sánchez-Fueyo1, Jane Tian2, Dominic Picarella2, Christoph Domenig1, Xin Xiao Zheng1, Catherine A Sabatos3, Natasha Manlongat4, Orissa Bender5, Thomas Kamradt5, Vijay K Kuchroo3, José-Carlos Gutiérrez-Ramos2, Anthony J Coyle2
& Terry B Strom1
1
Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
2
Inflammation Department, Experimental Medicine Division, Millennium Pharmaceuticals, Cambridge, Massachusetts 02116, USA.
3
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
4
Department of Haematology, Division of Investigative Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
5
Deutsches Rheumaforschungs Zentrum, Berlin D-10117, Germany.
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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