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- Title
XLP1 inhibitory effect by 2 B4 does not affect DNAM-1 and NKG2 D activating pathways in NK cells.
- Authors
Meazza, Raffaella; Tuberosa, Claudia; Cetica, Valentina; Falco, Michela; Loiacono, Fabrizio; Parolini, Silvia; Micalizzi, Concetta; Moretta, Alessandro; Mingari, Maria C.; Moretta, Lorenzo; Bottino, Cristina; Aricò, Maurizio; Pende, Daniela
- Abstract
X-linked lymphoproliferative disease 1 ( XLP1) is a rare congenital immunodeficiency caused by SH2 D1 A ( Xq25) mutations resulting in lack or dysfunction of SLAM-associated protein adaptor molecule. In XLP1 patients, upon ligand ( CD48) engagement, 2 B4 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 2 B4 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, 2 B4 affected both the cytolytic and IFN-γ production capabilities, functions that were restored upon disruption of the 2 B4/ CD48 interactions. Notably, we provide evidence that 2 B4 dysfunction does not affect the activity of DNAM-1 and NKG2 D triggering receptors. Thus, while CD48+ B- EBV and lymphoma B cells devoid of NKG2 D 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 2 B4 with triggering NK (and T) receptors.
- Publication
European Journal of Immunology, 2014, Vol 44, Issue 5, p1526
- ISSN
0014-2980
- Publication type
Article
- DOI
10.1002/eji.201344312