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.

Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients / Meazza, R.; Falco, M.; Marcenaro, S.; Loiacono, F.; Canevali, P.; Bellora, F.; Tuberosa, C.; Locatelli, F.; Micalizzi, C.; Moretta, A.; Mingari, M. C.; Moretta, L.; Arico, M.; Bottino, C.; Pende, D.. - In: EUROPEAN JOURNAL OF IMMUNOLOGY. - ISSN 0014-2980. - 47:6(2017), pp. 1051-1061. [10.1002/eji.201646885]

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

Locatelli F.;
2017

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.
2017
2B4; CD48; HLA class I; KIR; NK cells; NK receptors; NK-cell education; SAP; SLAM; XLP1
01 Pubblicazione su rivista::01a Articolo in rivista
Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients / Meazza, R.; Falco, M.; Marcenaro, S.; Loiacono, F.; Canevali, P.; Bellora, F.; Tuberosa, C.; Locatelli, F.; Micalizzi, C.; Moretta, A.; Mingari, M. C.; Moretta, L.; Arico, M.; Bottino, C.; Pende, D.. - In: EUROPEAN JOURNAL OF IMMUNOLOGY. - ISSN 0014-2980. - 47:6(2017), pp. 1051-1061. [10.1002/eji.201646885]
File allegati a questo prodotto
File Dimensione Formato  
Meazza_Inhibitory-2B4_2017.pdf

accesso aperto

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 1.42 MB
Formato Adobe PDF
1.42 MB Adobe PDF

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1479849
Citazioni
  • ???jsp.display-item.citation.pmc??? 9
  • Scopus 14
  • ???jsp.display-item.citation.isi??? 13
social impact