X-linked lymphoproliferative disease 1 (XLP1) is a monogenic disorder caused by mutations in SH2D1A, resulting in the absence/dysfunction of the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). Consequently, SLAM receptors as 2B4 (CD244) and NTB-A (SLAMF6), upon ligand engagement, exert inhibitory instead of activating function. This causes an immune dysfunction that is worsened by the selective inability of NK and T cells to kill EBV-infected B cells with dramatic clinical sequelae (e.g. fulminant mononucleosis, hyperinflammation, lymphoma). Here we outline recent findings on the interplay between inhibitory 2B4 and the various activating receptors in NK cells. 2B4 engagement selectively blocks ITAM-dependent activating receptors as NCR and CD16, while it does not affect NKG2D and DNAM-1. Furthermore, inhibitory 2B4 participates to NK cell education, as highlighted by the existence in XLP1 patients of a large subset of fully functional NK cells that lack self-HLA specific inhibitory receptors and exert autoreactivity against mature dendritic cells.

X连锁淋巴组织增生性疾病1（XLP1）是由SH2D1A中的突变引起的单基因疾病导致信号淋巴细胞活化分子（SLAM）相关蛋白（SAP）缺失/功能障碍。因此，SLAM受体（如2B4（CD244）和NTB-A（SLAMF6））在配体结合后发挥抑制作用而不是激活功能。这会导致免疫功能异常，这是由于NK和T细胞选择性地无力杀死具有严重临床后遗症（例如暴发性单核细胞增多症，过度炎症，淋巴瘤）的EBV感染的B细胞而加剧的。在这里，我们概述了抑制性2B4与NK细胞中各种激活受体之间相互作用的最新发现。2B4参与选择性地阻断依赖ITAM的激活受体（如NCR和CD16），而不会影响NKG2D和DNAM-1。此外，抑制性2B4参与NK细胞教育，