Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients. Issue 6 (5th May 2017)

• Record Type: Journal Article
• Authors: Meazza, Raffaella; Falco, Michela; Marcenaro, Stefania; Loiacono, Fabrizio; Canevali, Paolo; Bellora, Francesca; Tuberosa, Claudia; Locatelli, Franco; Micalizzi, Concetta; Moretta, Alessandro; Mingari, Maria C.; Moretta, Lorenzo; Aricò, Maurizio; Bottino, Cristina; Pende, Daniela
• Is Part Of: European journal of immunology. Volume 47:Issue 6(2017)
• Page Start: 1051
• Page End: 1061
• Publication Date: 2017-05-05
• Subjects: XLP1 -- SAP -- SLAM -- 2B4 -- CD48 -- NK cells -- KIR -- HLA class I -- NK receptors -- NK‐cell education; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.201646885
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract : In X‐linked lymphoproliferative disease 1 patients, the well‐represented self‐iNKR defective NK cells achieve functional competence through inhibitory 2B4 education. The 2B4/CD48 inhibitory pathway plays a major role in blocking lysis of CD48 + cells, impairing EBV infection resolution. Moreover, NK‐mediated killing of autologous mature dendritic cells (CD48 − ) can contribute to adaptive immunity dysfunction. 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.