Nature: TIM-3 mediates immunological tolerance

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Immunological tolerance, as a "double-edged sword", plays a dual role in the autoimmune disease and cancer. Scientists have discovered a new member in the study of anti-cancer families, and that is TIM-3. When part of the patients have resistance to PD-1 inhibitors, TIM-3 inhibitors can effectively overcome this adaptive resistance, and to be the new type of immunotherapy. So, what is TIM-3?

T cell immunoglobulin domain and mucin domain-3 (TIM-3) is a class of T cell surface inhibitory molecules, and it can cause T cell death after cancer and virus infection. Richard S. Blumberg team from Harvard Medical School has published the study on Nature. The authors firstly predict that TIM-3 could be co-expressed with CEACAM-1 located on the surface of T cells, afterwards, it is confirmed that the interaction of Ceacam-1 and TIM-3 inhibits the immune response of T cells to cancer cells by in-vitro stimulation, genetics and immunological methods, and then leads to the immunological tolerance of T cells to various diseases.

TIM-3 was firstly discovered in 2002 when scientists studied the novel gene family in asthma susceptibility genes, and it was initially thought to be specifically expressed on the T cell surface. The human TIM family includes TIM-1, TIM-3 and TIM-4, and they are located in chromosome 5 on the 5q33. As shown in Fig.1, common structures of TIM molecule include: immunoglobulin N-terminal mucin domain, transmembrane and intracellular region.

It has been reported that TIM-3 is highly expressed in Th1 cells and Tc1 cells, and it produces inhibitory signals that lead to cell apoptosis. Galectin 9 (Gal-9) as its ligand is a widely expressed soluble molecule that specifically binds to oligosaccharides on its immunoglobulin variable region, leads to negative regulatory effect of Th1-driven immune response. Meanwhile, TIM-3 is also highly expressed in human glioma (GBM) cells, as well as in T cells that have resistance to PD-1 inhibitors. Fig.2 shows the current study of TIM-3 involved in cell immunological tolerance.

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