TIM-3 (T cell immunoglobulin and mucin domain-3), also known as HAVCR2, is a 60 kDa member of the TIM family of immune regulating molecules. TIMs are type I transmembrane glycoproteins with one Ig-like V-type domain and a Ser/Thr-rich mucin stalk region. Mature mouse TIM-3 consists of a 174 amino acid (aa) extracellular domain (ECD), a 21 aa transmembrane segment, and a 67 aa cytoplasmic tail. Within the ECD, mouse TIM-3 shares 58% and 75% aa sequence identity with human and rat TIM-3, respectively. Recently, the identification of Galectin-9 as a ligand for TIM-3 has established the TIM-3-Galectin-9 pathway as an important regulator of Th1 immunity and tolerance induction. Engagement of Tim-3 by its ligand galectin-9 negatively regulates IFN-gamma secretion and influences the ability to induce T cell tolerance in both mice and man. The TIM-3-galectin-9 pathway could underlie chronic autoimmune disease states, such as multiple sclerosis. Numerous studies have demonstrated that Tim-3 influences autoimmune diseases, including diabetes and multiple sclerosis, and its role in other inflammatory diseases including allergies and cancer is beginning to become clear. In the tumor rejection model, the soluble form of Tim-3 (sTim-3) significantly impaired T cell antitumor immunity, evidenced by decreased antitumor CTL activity and reduced amount of tumor-infiltrating lymphocytes in the tumor.

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