{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNECTIN2—also known as CD112 or PVRL2—plays a central role in immune regulation by serving as a critical ligand for receptors expressed on natural killer (NK) cells and T cells. It binds the activating receptor DNAM‐1 (CD226) to promote cytotoxicity against stressed or malignant cells, as demonstrated by enhanced NK‐mediated lysis when NECTIN2 is present on target cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, high NECTIN2 expression on tumor targets and leukemic blasts can induce receptor cross‐linking that paradoxically leads to downregulation of DNAM‐1 on NK cells, thereby contributing to tumor escape"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ";."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In parallel, NECTIN2 is recognized by the inhibitory receptor TIGIT, and its binding—characterized by moderate micromolar affinity—further modulates cytotoxic responses under inflammatory and tumor microenvironment conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Recent immunotherapy approaches have even linked the blockade of NECTIN2-mediated interactions with enhanced anti-leukemic effects, underscoring its relevance in modulating effector cell functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond immune regulation, NECTIN2 functions as a cell adhesion molecule and viral receptor. Its extracellular immunoglobulin-like domain mediates both homophilic and heterophilic interactions that support the formation of adherens junctions and the proper organization of cell–cell contacts."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " The high-resolution crystallographic analysis of its V domain has provided insight into how charged residues control the affinity of NECTIN2 homodimers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " In addition, NECTIN2 participates in regulating vascular permeability—for example in the corpus luteum—and facilitates leukocyte transendothelial migration via heterophilic interactions with NECTIN3 on lymphocytes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " Moreover, in the context of viral infections, NECTIN2 functions as an entry receptor for alphaherpesviruses, and experimental studies with soluble forms of NECTIN2 show that its accumulation can reduce viral propagation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " Its direct interactions with classical adhesion molecules such as N-cadherin further support the maintenance of tissue architecture"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", while transgenic expression studies highlight its complex role during herpes simplex virus infection."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic, posttranslational, and tumor cell–intrinsic aspects of NECTIN2 further underscore its multifaceted functions in health and disease. Genetic polymorphisms and chromosomal rearrangements involving the NECTIN2 (PVRL2) gene are associated with diverse pathologies, including coronary heart disease"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": ", nonsyndromic orofacial clefts"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", and multiple sclerosis severity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " In various cancers, including colon carcinoma, ovarian cancer, diffuse large B-cell lymphoma, and acute myeloid leukemia, aberrant NECTIN2 expression—whether through enhanced transcription, dysregulated posttranslational ubiquitination, or gene fusion events—can influence tumor cell adhesion, metastasis, and immune evasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "27"}]}, {"type": "t", "text": " In addition, NECTIN2 levels correlate with prognosis and have been linked to disease outcomes in acute myeloid leukemia and neuroblastoma, while its regulation via ubiquitination modulates tumor susceptibility to NK cell–mediated lysis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "28", "end_ref": "30"}]}, {"type": "t", "text": " Epigenetic studies also implicate NECTIN2 in longevity and neurodegenerative processes, including Alzheimer’s disease, and its role in the brain has been associated with synapse formation and homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "33"}]}, {"type": "t", "text": " Finally, altered NECTIN2 expression in chronic lymphocytic leukemia has been linked to T-cell exhaustion, and studies in colon carcinoma further underscore its relevance as a potential diagnostic and prognostic marker."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "34", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Cristina Bottino, Roberta Castriconi, Daniela Pende, et al. 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