PVRL2

Official Full Name

nectin cell adhesion molecule 2

Organism

Homo sapiens

GeneID

5819

Background

This gene encodes a single-pass type I membrane glycoprotein with two Ig-like C2-type domains and an Ig-like V-type domain. This protein is one of the plasma membrane components of adherens junctions. It also serves as an entry for certain mutant strains of herpes simplex virus and pseudorabies virus, and it is involved in cell to cell spreading of these viruses. Variations in this gene have been associated with differences in the severity of multiple sclerosis. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

Synonyms

NECTIN2; HVEB; PRR2; CD112; PVRL2; PVRR2;

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Detailed Information

The NECTIN2 gene, also known as CD112, is located on human chromosome 19q13.32 and encodes a single-pass type I transmembrane glycoprotein. Structurally, NECTIN2 belongs to the immunoglobulin superfamily, with its extracellular domain composed of two C2-type immunoglobulin-like domains followed by a V-type immunoglobulin-like domain. This canonical arrangement underlies its role in mediating cell–cell recognition and adhesion. NECTIN2 is a key component of adherens junctions and is widely expressed in various epithelial and endothelial cells. It forms stable trans-interactions with NECTIN molecules on adjacent cells or other adhesion molecules, contributing to the maintenance of tissue integrity, cell polarity, and barrier function. Alternative splicing of NECTIN2 generates multiple protein isoforms with functional diversity, allowing it to adapt to the specific requirements of different cell types and physiological contexts.

Biological Significance

NECTIN2's biological roles span two interconnected but distinct domains: cell–cell adhesion and immune regulation. As a classical adhesion molecule, NECTIN2 mediates homophilic and heterophilic interactions, including with other family members such as NECTIN3, stabilizing cadherin-mediated adherens junctions. This function is essential for embryogenesis, tissue morphogenesis, and epithelial homeostasis.

Figure 1. Nectin-2 expression in the testis and olfactory epithelium. (Mizutani K, et al. 2022)

In immune regulation, NECTIN2 is expressed on antigen-presenting cells and certain tumor cells, serving as a ligand for multiple T cell surface receptors. When NECTIN2 binds the activating receptor CD226 on T cells, it provides a co-stimulatory signal that promotes T cell proliferation and production of key cytokines such as interleukin-2 and interferon-γ, enhancing antiviral and antitumor responses. Conversely, interaction with the inhibitory receptor PVRIG transmits a co-inhibitory signal that suppresses T cell proliferation and effector function. Notably, NECTIN2 binding to CD226 and PVRIG is competitive, meaning that the relative expression and affinity of these receptors in the local microenvironment determine whether T cell signaling is activating or inhibitory. This positions NECTIN2 as a dynamic, context-dependent immune "switch." Additionally, NECTIN2 serves as a receptor for certain herpesvirus strains, mediating viral entry and cell-to-cell spread, highlighting its significance at the cell membrane interface.

Clinical Relevance

NECTIN2's clinical relevance spans infectious diseases, autoimmunity, and cancer immunotherapy. In infectious diseases, NECTIN2 acts as an entry point for pathogens such as herpes simplex virus and pseudorabies virus, and interventions targeting this pathway could theoretically block viral infection. In autoimmune disorders, genome-wide association studies have linked NECTIN2 variants to multiple sclerosis severity, consistent with its role in T cell regulation; dysregulated NECTIN2 signaling may impair immune tolerance and exacerbate autoimmune pathology.

NECTIN2 is particularly notable in cancer immunotherapy. Many tumors upregulate NECTIN2 to exploit its inhibitory signaling via PVRIG on T cells, thereby suppressing tumor-infiltrating lymphocyte activity and promoting immune evasion. Development of monoclonal antibodies targeting the NECTIN2–PVRIG interaction is an emerging strategy, aiming to relieve immunosuppression in the tumor microenvironment. Such therapies may act synergistically with existing PD-1/PD-L1 checkpoint inhibitors and offer new options for patients who do not respond to current treatments. Ongoing clinical trials targeting PVRIG or multiple related pathways have shown promising safety and preliminary antitumor activity. Beyond therapy, soluble NECTIN2 or its expression levels in biofluids may serve as potential biomarkers for predicting immunotherapy response or disease prognosis.

References

Reymond N, Imbert AM, Devilard E, et al. DNAM-1 and PVR regulate monocyte migration through endothelial junctions. J Exp Med. 2004;199(9):1331–1341.
Mizutani K, Miyata M, Shiotani H, et al. Nectin-2 in general and in the brain. Mol Cell Biochem. 2022 Jan;477(1):167-180.
Zhu Y, Paniccia A, Schulick AC, et al. Identification of CD112R as a novel checkpoint for human T cells. J Exp Med. 2016;213(1):167–176.
Whelan S, Ophir E, Kotturi MF, et al. PVRIG is a novel NK cell immune checkpoint receptor in acute myeloid leukemia. J Clin Invest. 2021;131(21):e146364.

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