XLP1 inhibitory effect by 2B4 does not affect DNAM-1 and NKG2D activating pathways in NK cells.
X-linked lymphoproliferative disease 1 (XLP1) is a rare congenital immunodeficiency caused by SH2D1A (Xq25) mutations resulting in lack or dysfunction of SLAM-associated protein adaptor molecule. In XLP1 patients, upon ligand (CD48) engagement, 2B4 delivers inhibitory signals that impair the cytolytic activity of NK (and T) cells. This causes the selective inability to control EBV infections and the occurrence of B-cell lymphomas. Here, we show that in the absence of SLAM-associated protein, co-engagement of 2B4 with different activating receptors, either by antibodies or specific ligands on target cells, inhibits different ITAM-dependent signaling pathways including activating killer Ig-like receptors. In XLP1 NK cells, 2B4 affected both the cytolytic and IFN-γ production capabilities, functions that were restored upon disruption of the 2B4/CD48 interactions. Notably, we provide evidence that 2B4 dysfunction does not affect the activity of DNAM-1 and NKG2D triggering receptors. Thus, while CD48(+) B-EBV and lymphoma B cells devoid of NKG2D and DNAM-1 ligands were resistant to lysis, the preferential usage of these receptors allowed XLP1 NK cells to kill lymphomas that expressed sufficient amounts of the specific ligands. The study sheds new light on the XLP1 immunological defect and on the cross-talk of inhibitory 2B4 with triggering NK (and T) receptors.
Istituto di Ricovero e Cura a Carattere Scientifico Azienda Ospedaliera Universitaria San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
Raffaella
R
Meazza
Claudia
C
Tuberosa
Valentina
V
Cetica
Michela
M
Falco
Fabrizio
F
Loiacono
Silvia
S
Parolini
Concetta
C
Micalizzi
Alessandro
A
Moretta
Maria C
MC
Mingari
Lorenzo
L
Moretta
Cristina
C
Bottino
Maurizio
M
Aricò
Daniela
D
Pende
D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D000071178:CD48 Antigen; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000071176:Signaling Lymphocytic Activation Molecule Family; D000098862:T Lineage-Specific Activation Antigen 1
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; C084093:CD244 protein, human; D000071178:CD48 Antigen; C000604065:CD48 protein, human; C573415:IFNG protein, human; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D007371:Interferon-gamma
2B4; Ligands; NK cells; Triggering receptors; XLP1