Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients

Raffaella Meazza, Michela Falco, Stefania Marcenaro, Fabrizio Loiacono, Paolo Canevali, Francesca Bellora, Claudia Tuberosa, Franco Locatelli, Concetta Micalizzi, Alessandro Moretta, Maria C Mingari, Lorenzo Moretta, Maurizio Aricò, Cristina Bottino, Daniela Pende

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1051-1061
Number of pages11
JournalEuropean Journal of Immunology
Issue number6
Publication statusPublished - Jun 2017


  • CD48 Antigen
  • Genes, MHC Class I
  • Humans
  • Killer Cells, Natural
  • Lymphocyte Activation
  • Lymphoproliferative Disorders
  • Potassium Channels, Inwardly Rectifying
  • Receptors, Immunologic
  • Receptors, Natural Killer Cell
  • Signal Transduction
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Signaling Lymphocytic Activation Molecule Family
  • Journal Article
  • Research Support, Non-U.S. Gov't


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