Nature Immunology4, 1102 - 1110 (2003)
Published online: 12 October 2003; | doi:10.1038/ni988
Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance
Catherine A Sabatos1, Sumone Chakravarti1, Eugene Cha1, Anna Schubart1, Alberto Sánchez-Fueyo2, Xin Xiao Zheng2, Anthony J Coyle3, Terry B Strom2, Gordon J Freeman4
& Vijay K Kuchroo1
1
Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
2
Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
3
Inflammation Department, Experimental Medicine Division, Millennium Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
4
Department of Medical Oncology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
T helper type 1 (TH1) immune responses are central in cell-mediated immunity, and a TH1-specific cell surface molecule called Tim-3 (T cell immunoglobulin domain, mucin domain) has been identified. Here we report the identification of a secreted form of Tim-3 that contains only the immunoglobulin (Ig) variable (V) domain of the full-length molecule. Fusion proteins (Tim-3−Ig) of both Tim-3 isoforms specifically bound CD4+ T cells, indicating that a Tim-3 ligand is expressed on CD4+ T cells. Administration of Tim-3−Ig to immunized mice caused hyperproliferation of TH1 cells and TH1 cytokine release. Tim-3−Ig also abrogated tolerance induction in TH1 cells, and Tim-3-deficient mice were refractory to the induction of high-dose tolerance. These data indicate that interaction of Tim-3 with Tim-3 ligand may serve to inhibit effector TH1 cells during a normal immune response and may be crucial for the induction of peripheral tolerance.
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