HAVCR2 Gene

The HAVCR2 gene (HAVCR2 stands for "Hepatitis A Virus Cellular Receptor 2") is a protein-coding gene located on chromosome 5q33.3.

The protein encoded by this gene, Hepatitis A Virus Cellular Receptor 2 (also referred to as TIM-3 ), is a cell surface receptor involved in modulating innate and adaptive immune responses. It is thought to have an inhibitory function. Reports of stimulatory functions suggest that activity may be influenced by cellular context and/or the particular ligand (Gorman JV et al. 2014).

HAVCR2 protein regulates macrophage activation (Monney L et al 2002). Inhibits T helper type 1 lymphocyte (Th1) mediated autoimmune and alloimmune responses and promotes immunological tolerance (Sánchez-Fueyo A et al 2003). In CD8+ cells, it attenuates TCR-induced signaling, particularly by blocking NF-kappaB and NFAT promoter activities, resulting in loss of IL-2 secretion. In contrast, it has been shown to activate TCR-induced signaling in T cells, likely involving ZAP70, LCP2, LCK, and FYN. The receptor protein is expressed on Treg cells and can inhibit Th17 cell responses (Gautron AS et al. 2014).

HAVCR2 appears to serve as a receptor for LGALS9 (galectin 9). Binding to LGALS9 is thought to lead to suppression of T cell responses; the resulting apoptosis of antigen-specific cells may be related to phosphorylation of HAVCR2 and disruption of its association with BAG6.

Furthermore, the receptor protein is expressed on Th1 cells and interacts with LGALS9 expressed on Mycobacterium tuberculosis-infected macrophages to stimulate antibacterial activity, including IL-1 beta secretion, and limit intracellular bacterial growth.

HAVCR2 can recognize PtSer on apoptotic cells, leading to their phagocytosis. HAVCR2 mediates the uptake of apoptotic cells by dendritic cells. The receptor protein is expressed on T cells and promotes conjugation but not engulfment of apoptotic cells. It is expressed on dendritic cells (DCs) and natural killer (NK) cells, positively regulates the innate immune response, and promotes secretion of TNF-alpha in synergy with Toll-like receptors. In tumor-infiltrating DCs, it suppresses the nucleic acid-mediated innate immune response by interacting with HMGB1 and interfering with nucleic acid recognition and transport to endosomes. In contrast, it has been shown to suppress NK cell-mediated cytotoxicity (Ndhlovu LC et al. 2012).

The protein encoded by this gene belongs to the immunoglobulin superfamily and the TIM family of proteins. CD4-positive T helper lymphocytes can be divided into types 1 (Th1) and 2 (Th2) based on their cytokine secretion patterns. Th1 cells are involved in cell-mediated immunity against intracellular pathogens and in delayed-type hypersensitivity reactions, whereas Th2 cells are involved in fighting extracellular helminthic infections and promoting atopic and allergic diseases. This protein is a Th1-specific cell surface protein that regulates macrophage activation, inhibits Th1-mediated autoimmune and alloimmune responses, and promotes immunological tolerance.

Diseases associated with HAVCR2 include:

• Subcutaneous Panniculitis-Like T-Cell Lymphoma (OMIM: 618398)

and

• Hepatitis A (HAVCR2, along with HAVCR1, is a receptor for hepatitis A virus).

1. Gautron AS et al (2014) Enhanced suppressor function of TIM-3+ FoxP3+ regulatory T cells. Eur J Immunol 44:2703-2711.
2. Gorman JV et al (2014) Regulation of T cell responses by the receptor molecule Tim-3. Immunol Res 59: 56-65.
3. Monney L et al (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415:536-541.
4. Ndhlovu LC et al (2012) Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood 119: 3734-3743.
5. Sánchez-Fueyo A et al (2003) Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol 4:1093-1101.