title: Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients.
abstract: X-linked lymphoproliferative disease 1 (XLP1) is an inherited immunodeficiency, caused by mutations in SH2D1A encoding Signaling Lymphocyte Activation Molecule (SLAM)-associated protein (SAP). In XLP1, 2B4, upon engagement with CD48, has inhibitory instead of activating function. This causes a selective inability of cytotoxic effectors to kill EBV-infected cells, with dramatic clinical sequelae. Here, we investigated the NK cell education in XLP1, upon characterization of killer Ig-like receptor (KIR)/KIR-L genotype and phenotypic repertoire of self-HLA class I specific inhibitory NK receptors (self-iNKRs). We also analyzed NK-cell cytotoxicity against CD48+or CD48-KIR-ligand matched or autologous hematopoietic cells in XLP1 patients and healthy controls. XLP1 NK cells may show a defective phenotypic repertoire with substantial proportion of cells lacking self-iNKR. These NK cells are cytotoxic and the inhibitory 2B4/CD48 pathway plays a major role to prevent killing of CD48+EBV-transformed B cells and M1 macrophages. Importantly, self-iNKR defective NK cells kill CD48-targets, such as mature DCs. Self-iNKR-NK cells in XLP1 patients are functional even in resting conditions, suggesting a role of the inhibitory 2B4/CD48 pathway in the education process during NK-cell maturation. Killing of autologous mature DC by self-iNKR defective XLP1 NK cells may impair adaptive responses, further exacerbating the patients' immune defect.
authors.affiliation: Dipartimento delle Terapie Oncologiche Integrate, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Meazza
authors.affiliation: Dipartimento di Ricerca e Diagnostica, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Falco
authors.affiliation: Dipartimento di Ricerca e Diagnostica, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Marcenaro
authors.affiliation: Dipartimento delle Terapie Oncologiche Integrate, IRCCS AOU San Martino-IST, Genoa, Italy.|Dipartimento di Ricerca e Diagnostica, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Loiacono
authors.affiliation: Dipartimento di Ricerca e Diagnostica, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Canevali
authors.affiliation: Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bellora
authors.affiliation: Dipartimento delle Terapie Oncologiche Integrate, IRCCS AOU San Martino-IST, Genoa, Italy.|Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Tuberosa
authors.affiliation: Dipartimento di Oncoematologia Pediatrica, IRCCS Ospedale Bambino Gesù, Rome, Italy.|Università di Pavia, Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Dipartimento di Oncoematologia Pediatrica, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Micalizzi
authors.affiliation: Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Moretta
authors.affiliation: Dipartimento delle Terapie Oncologiche Integrate, IRCCS AOU San Martino-IST, Genoa, Italy.|Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Mingari
authors.affiliation: Dipartimento dei Laboratori, Area di Ricerca di Immunologia, IRCCS Ospedale Bambino Gesù, Rome, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moretta
authors.affiliation: Azienda Sanitaria Provinciale, Ragusa, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Aricò
authors.affiliation: Dipartimento di Ricerca e Diagnostica, IRCCS Istituto Giannina Gaslini, Genoa, Italy.|Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genoa, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bottino
authors.affiliation: Dipartimento delle Terapie Oncologiche Integrate, IRCCS AOU San Martino-IST, Genoa, Italy.
authors.forename: Daniela
authors.identifier: 0000-0003-1565-451X
authors.initials: D
authors.lastname: Pende
mesh_terms: D000071178:CD48 Antigen / Q000276:immunology / Q000378:metabolism; D005805:Genes, MHC Class I; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000276:immunology* / Q000503:physiopathology*; D024661:Potassium Channels, Inwardly Rectifying / Q000276:immunology; D011971:Receptors, Immunologic / Q000378:metabolism; D055607:Receptors, Natural Killer Cell / Q000276:immunology*; D015398:Signal Transduction; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein / Q000378:metabolism; D000071176:Signaling Lymphocytic Activation Molecule Family / Q000276:immunology / Q000378:metabolism*; D000098854:Kcnj10 Channel
chemical_list: C084093:CD244 protein, human; D000071178:CD48 Antigen; C000604065:CD48 protein, human; D000098854:Kcnj10 Channel; D024661:Potassium Channels, Inwardly Rectifying; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family
keywords: 2B4; CD48; HLA class I; KIR; NK cells; NK receptors; NK-cell education; SAP; SLAM; XLP1