TIM3

TIM-3, also known as HAVCR2, is an immune checkpoint receptor that belongs to the T cell immunoglobulin and mucin-domain-containing (TIM) family. It is expressed on subsets of T cells, particularly exhausted Th1 and cytotoxic T cells, as well as on natural killer cells, dendritic cells, and some myeloid cells. The protein features an extracellular immunoglobulin V-like domain and a mucin domain, with a cytoplasmic tail that transmits signals upon ligand engagement.

TIM-3 functions as a negative regulator of immune responses. In chronic infections and cancer, TIM-3 is upregulated and contributes to T cell exhaustion, reducing proliferation and effector cytokine production. It also participates in maintaining peripheral tolerance and preventing autoimmunity through regulation of innate and adaptive immune activities. The balance of TIM-3 signaling influences the overall magnitude and quality of immune responses in various contexts.

Ligands described for TIM-3 include galectin-9, which is the best-characterized ligand, and phosphatidylserine exposed on apoptotic cells; additional proposed ligands have been reported in different settings, though evidence varies. Engagement of TIM-3 can inhibit T cell receptor signaling, with modulation of signaling influenced by interactions in the cytoplasmic tail and associations with intracellular partners such as BAT3.

Clinical relevance and research: TIM-3 is a target of interest in cancer immunotherapy, with several anti-TIM-3 antibodies evaluated in clinical trials, often in combination with PD-1 or PD-L1 inhibitors to reinvigorate exhausted T cells. TIM-3 expression and soluble TIM-3 levels are also explored as biomarkers in a range of diseases, including chronic infections and autoimmune conditions. As of now, TIM-3–targeted therapies are under investigation rather than approved therapies.