HAVCR2


Hepatitis A virus cellular receptor 2, also known as T-cell immunoglobulin and mucin-domain containing-3, is a protein that in humans is encoded by the HAVCR2 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.

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 and a glycosylated mucin domain of variable length located closer to the membrane. Intracellular domain of HAVCR2 is called C-terminal cytoplasmic tail. It contains five conserved tyrosine residues that interact with multiple components of T-cell receptor complex and negatively regulates its function.

Function

HAVCR2 is an immune checkpoint and together with other inhibitory receptors including programmed cell death protein 1 and lymphocyte activation gene 3 protein mediate the CD8+ T-cell exhaustion. HAVCR2 has also been shown as a CD4+ Th1-specific cell surface protein that regulates macrophage activation and enhances the severity of experimental autoimmune encephalomyelitis in mice.
HAVCR2 is primarily activated by galectin-9. The engagement leads to stimulation of an influx of calcium to intracellular space and induction of programmed cell death, apoptosis. As a consequence, a suppression of Th1 and Th17 responses and induction of immune tolerance occurs. In addition to galectin-9, a couple other ligands have been identified, such as phospatidyl serine, High Mobility Group Protein 1 and Carcinoembryonic Antigen Related Cell Adhesion Molecule 1. The binding of PtdSer has been shown to cause an uptake of apoptotic cells and reduced cross presentation of dying cell-associated antigens by dendritic cells. The binding of HMGB1 can interfere with nucleic acid stimulation and suppresses activation of innate immune response. The role of CEACAM1 engagement is still not clear.

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 in combination with anti-PD-1 or anti-PD-L1 therapies are ongoing.
The role of HAVCR2 in the T-cell dysfunction has been investigated in chronic viral infections.