HAVCR2 is called C-terminal cytoplasmic tail. It contains five conserved tyrosine residues that interact with multiple components of T-cell receptor (TCR) complex, mediates intercellular signaling pathways and negatively regulates its function. Function HAVCR2/TIM-3 is a transmembrane protein of T lymphocytes (CD4+ and CD8+ T cells), myeloid cells (monocytes, macrophages, DC, mast cells, NK cells) or various cells in different tumor types. The receptor is an immune checkpoint and together with other inhibitory receptors including programmed cell death protein 1 (PD-1) and lymphocyte activation gene 3 protein (LAG3) mediate the CD8+ T-cell exhaustion in terms of proliferation and secretion of cytokines such as TNF-alpha, IFN-gamma and IL-2. Combined blockade of HAVCR2 and PD-1 led to improved CD8+ T-cell response during the lymphocytic choriomeningitis virus infection. HAVCR2 and PD-1 may be responsible for NK cell exhaustion as well. HAVCR2 has also been shown as a CD4+ Th1-specific cell surface protein that regulates macrophage activation, regulates the production of cytokines and enhances the severity of experimental autoimmune encephalomyelitis in mice. Is also known the free form of HAVCR2 outside the cell membrane (soluble form), lacking mucin and the transmembrane domain. However, the function of the soluble protein is unknown. Ligands Gal-9 HAVCR2 is primarily activated by soluble galectin-9. The engagement leads to stimulation of an influx of calcium to intracellular space and induction of programmed cell death, apoptosis, cell necrosis or T cell anergy. As a consequence, a suppression of Th1 and Th17 responses and induction of immune tolerance occurs, gal-9/HAVCR2 increases the immunosuppressive activity of Treg cells. In addition to galectin-9, several ligands have been identified, such as phosphatidylserine (PtdSer), High Mobility Group Protein 1 (HMGB1) and Carcinoembryonic Antigen Related Cell Adhesion Molecule 1 (CEACAM1). PtdSer PtdSer is exposed on the surface of apoptotic cells and binds through the FG loop in the IgV domain. The binding of PtdSer with TIM-3 receptor has been shown to cause an uptake of apoptotic cells and is responsible for the cross-presentation of dying cell-associated antigens by dendritic cells. PtdSer binds to the opposite side of the IgV domain of TIM-3 than Gal-9, and although this interaction of PtdSer to TIM-3 has five times less affinity than other members of the TIM family, Tim-3 can also bind some other ligand to phagocytose apoptotic cells. HMGB1 HMGB1 is alarmin and interacts with DNA released from dying cells or pathogen nucleid acid, facilitating absorption by cell and increasing