T-cell immunoglobulin and mucin domain 3 (TIM3) is a molecule selectively expressed on T helper 1 (Th1) cells. It is an immune checkpoint receptor that suppresses the activation of Th1 cells on engagement with its ligand, galectin-9.
cell immunoglobulin and mucin domain 3 (TIM3) is a member of Tim family, which consists of 301 amino acids. The common structure of TIM3 molecules includes: variable region of N-terminal immunoglobulin, mucin domain, transmembrane region and intracellular region. At the same time, TIM3, as an immunological checkpoint, plays an important role in the immunomodulation of tumor microenvironment.
Molecular biological characteristics of TIM3
TIM3 and cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death factor-1 (PD-1) and their ligands (PD-L) all belong to immunological checkpoint molecules, and They activate co-stimulatory signals during the cytotoxicity of the cellular immune system to tumor cells. TIM3 was selectively expressed in T helper cells (Th1 and Th17),T regulatory cells (Treg), dendritic cells (DCs) and monocytes. TIM3 can reduce inflammation by inhibiting macrophage polarization to M1 in autoimmune diseases. Symptomatic reaction and lymphocytic infiltration. It inhibits the activation of Th1 cells in phagocytes.
Galectin-9 is a ligand of TIM-3,which belongs to the galectin-9 family. Galectin-9 is linked to a peptide chain by two series sugar recognition domains (CRD), and hasβ-galactose binding activity, and it has been found that there are 14 subtypes. Galectin-9 has many biological functions, such as regulating cell aggregation and adhesion, tumor cell apoptosis and so on. When TIM3 binds to its ligand Galectin-9, it can inhibit Th1 and Th17 amplification, promote Th1 apoptosis, induce a large number of proliferation of Myeloid-derived suppressor cells (MDSC), thus directly or indirectly promote peripheral immune tolerance and inhibit body anti-tumor immunity.
Immunosuppressive effect of TIM3 in tumor microenvironment
As an important immunomodulator, TIM3 has a variety of immunomodulation: it participates in the apoptosis of Th1 and Th17 cells, promotes the proliferation of Treg cells and MDSC, and hinders the activation and differentiation of DCs. Blocking TIM3 signal or other co-stimulatory signals can effectively inhibit tumor growth.
Inhibition of Th1 cells
The main mechanism of Th1 cell apoptosis induced by TIM3: when Th0 cells differentiate into Th1 cells stimulated by interleukin-2 and overexpression of TIM3 molecules on Th1 cells, co-culture with recombinant TIM4 will form TIM3-TIM4 complex on the surface of Th1 cells. The complex promotes the phosphorylation of p300 in Th1 cells and up-regulates FasL, thus promoting the apoptosis of Th1 cells.
Promote Treg to become a highly immunosuppressive cell group
In tumor microenvironment, Treg cells expressing TIM3 molecules are highly immunosuppressed. Tumor infiltrating Treg inhibits Interferon-γ (IFN-γ) levels by secreting IL-10 in large quantities in patients with ovarian cancer and promotes tumor immune tolerance.
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Tao Jinglian, Li Lijuan, Shao Zonghong.(2016).Progress in the role of TIM3 in tumor microenvironment. Chinese Journal of Immunology.32(07);1070-1073