Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance

Nat Immunol. 2003 Nov;4(11):1102-10. doi: 10.1038/ni988. Epub 2003 Oct 12.


T helper type 1 (T(H)1) immune responses are central in cell-mediated immunity, and a T(H)1-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 T(H)1 cells and T(H)1 cytokine release. Tim-3-Ig also abrogated tolerance induction in T(H)1 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 T(H)1 cells during a normal immune response and may be crucial for the induction of peripheral tolerance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies / genetics
  • Antibodies / metabolism
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Division / immunology
  • Cell Division / physiology
  • Hepatitis A Virus Cellular Receptor 2
  • Immune System / immunology*
  • Immune Tolerance / immunology
  • Ligands
  • Protein Isoforms
  • Receptors, Virus / genetics
  • Receptors, Virus / metabolism*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • Th1 Cells / immunology
  • Th1 Cells / metabolism*


  • Antibodies
  • Havcr2 protein, mouse
  • Hepatitis A Virus Cellular Receptor 2
  • Ligands
  • Protein Isoforms
  • Receptors, Virus
  • Recombinant Fusion Proteins