The immunoglobulin superfamily member Tim3 (T-cell immunoglobulin mucin 3) was first identified as a cell-surface marker preferentially expressed by T helper 1 (TH1) cells, but the in vivo functions of Tim3 have remained unknown. Two papers now published in Nature Immunology show that Tim3 regulates TH1-cell-mediated immune responses and is important for tolerance induction.
To investigate the function of Tim3, Sabatos et al. generated soluble fusion proteins in which mouse Tim3 was fused to the Fc portion of human immunoglobulin. Administration of Tim3–immunoglobulin fusion proteins during a TH1-cell-mediated immune response led to hyperproliferation of TH1 cells and increased production of TH1-type cytokines, indicating that Tim3 normally acts to inhibit TH1-cell effector responses.
Early studies using Tim3-specific monoclonal antibodies indicated that Tim3 acts as a negative regulator of autoimmune responses. To investigate this further, Sánchez-Fueyo et al. studied the effects of blocking the Tim3 pathway in NOD mice (which spontaneously develop insulin-dependent diabetes). Treatment with Tim3-specific monoclonal antibodies accelerated the onset of disease in these mice, confirming earlier reports of a role for this protein in inhibiting autoimmune responses.
Both groups investigated the role of Tim3 in the induction of tolerance. Blockade of the Tim3 pathway (either through treatment with Tim3–immunoglobulin fusion proteins or genetic targeting of Tim3) prevented the development of both transplantation tolerance and peripheral tolerance induced with high doses of antigen. Further experiments by Sánchez-Fueyo et al. showed that Tim3 normally promotes the induction of tolerance, in part, due to effects on CD4+CD25+ regulatory T cells.
References
ORIGINAL RESEARCH PAPERS
Sabatos, C. A. et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nature Immunol. 12 October 2003 (DOI: 10.1038/ni988)
Sánchez-Fueyo, A. et al. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nature Immunol. 12 October 2003 (DOI: 10.1038/ni987)
FURTHER READING
Kuchroo, V. K. et al. The TIM gene family: emerging roles in immunity and disease. Nature Rev. Immunol. 3, 454–462 (2003)
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Buckland, J. Tim3 – tolerance's little helper!. Nat Rev Immunol 3, 844 (2003). https://doi.org/10.1038/nri1235
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DOI: https://doi.org/10.1038/nri1235