Hepatitis A virus cellular receptor 2 (HAVCR2), also known as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), is a protein that in humans is encoded by the HAVCR2 (TIM-3)gene. HAVCR2 was first described in 2002 as a cell surface molecule expressed on IFNγ producing CD4+ Th1 and CD8+ Tc1 cells. Later, the expression was detected in Th17 cells, regulatory T-cells, and innate immune cells (dendritic cells, NK cells, monocytes). HAVCR2 receptor is a regulator of the immune response. Discovery In a screen to identify differentially expressed molecules between Th1 and Th2 cells, Vijay Kuchroo and colleagues first described HAVCR2/TIM-3 in 2002. Kuchroo was the first to characterize the inhibitory function of TIM-3 and its role in inhibiting T cell responses in both autoimmunity and cancer. Similar to other checkpoint inhibitors such as PD-1 and CTLA-4, TIM-3 has been successfully targeted to treat several solid and hematogenous malignancies, including melanoma, AML, and MDS. Classification HAVCR2 /TIM-3 is member of TIM immunoregulatory proteins family which is encoded by gene on mouse chromosome 11B1.1 and on human chromosome 5q33.2. This chromosomal region has been repeatedly linked with asthma, allergy and autoimmunity. The TIM gene family include another eight members (TIM-1–8) on mouse chromosome and three members (TIM-1, TIM-3 and TIM-4) on human chromosome. Structure HAVCR2 belongs to TIM family cell surface receptor proteins. These proteins share a similar structure, in which the extracellular region consists of membrane distal single variable immunoglobulin domain (IgV), a glycosylated mucin domain of variable length located closer to the membrane transmembrane region, and intracellular stem. The IGV domain is form by two antiparallel beta sheets that are linked by disulfide bridges between four conserved cysteines. Cysteine bridges create a CC´ loop and an FG loop in the domain which make unique cleft characteristics for TIM-3 proteins. The cleft is stabilized by disulfide and hydrogen bonds and is a binding site for ligands such as CEACAM-1 and phosphatidylserine. The extracellular portion of the IgV domain may also be glycosylated and this glycan-binding sites is recognizes by carbohydrate domain of another ligands galectin-9 (Gal-9). The mucin domain is variable in a member of the TIM family, in TIM3 it is the smallest domain and has regions rich in serine, proline and threonine. This region also contains target sites for O- and N-linked glycosylation. The transmembrane domain anchors the HAVCR2 protein in the cytoplasmic membrane of the cell. The intracellular domain of