nucleic acid sensing by endosomal Toll-like receptors (TLRs). HMGB1 binds to HAVCRS2/TIM3 on dendritic cells but its binding site has not been determined. TIM-3 receptor prevents the entry of the nucleic acids into the cell and suppresses activation of TLR signaling in dendritic cells. So the binding of HMGB1suppresses activation of innate immune response. CEACAM1 The last known TIM3 receptor ligand is CEACAM1 glycoprotein. It is co-expressed with TIM3 T cells but also monocytes, macrophages, dendritic cells. It binds to the CC´ and FG loops of the TIM3 protein. CEACAM1 can also bind to TIM3 intracellularly (cis presentation) and is likely to be important for TIM-3 maturation on cell surface. The CEACAM1 binding contributes to the development of T cell tolerance, triggers the release of BAT3 from TIM-3 leading to inhibition of TCR signaling, and also inhibits the immune response of myeloid cells. Clinical significance HAVCR2 expression is up regulated in tumor-infiltrating lymphocytes in lung, gastric, head and neck cancer, schwannoma, melanoma and follicular B-cell non-Hodgkin lymphoma. The HAVCR2 pathway may interact with the PD-1 pathway in the dysfunctional CD8+ T cells and Tregs in cancer. HAVCR2 is mainly expressed on activated CD8+ T cells and suppresses macrophage activation following PD-1 inhibition. Upregulation was observed in tumors progressing after anti-PD-1 therapy. This seems to be a form of adaptive resistance to immunotherapy. Multiple phase 1/2 clinical trials with anti-HAVCR2 monoclonal antibodies (LY3321367, Eli Lilly and Company; MBG453, Novartis Pharmaceuticals; TSR-022, Tesaro, Inc.) in combination with anti-PD-1 or anti-PD-L1 therapies are ongoing. HAVCR2 is also an exhaustion maker for NK cells. Blockade of this receptor can improve the NK cells antitumor activity in esophageal cancer, melanoma and lung adenocarcinoma. The role of HAVCR2 in the T-cell dysfunction has been investigated in chronic viral infections. Together with PD-1, HAVCR2 negatively regulate CD8+ T-cells and thus, in vivo blockade of HAVCR2 and PD-1 led to the restoring of antiviral immunity. A recent genome-wide association study (GWAS) has found that genetic variations in HAVCR2 are associated with late-onset sporadic Alzheimer's disease (LOAD). HARVC2 is capable of interacting with amyloid-β precursor protein. References