Cutting Edge: Functional Requirement for SAP in 2B4-Mediated Activation of Human Natural Killer Cells as Revealed by the X-Linked Lymphoproliferative Syndrome

Abstract

X-linked lymphoproliferative syndrome (XLP) is an immunodeficiency characterized by life-threatening infectious mononucleosis and EBV-induced B cell lymphoma. The gene mutated in XLP encodes SLAM (signaling lymphocytic activation molecule-associated protein)-associated protein (SAP), a small SH2 domain-containing protein. SAP associates with 2B4 and SLAM, activating receptors expressed by NK and T cells, and prevents recruitment of SH2 domain-containing protein tyrosine phosphatase-2 SHP-2) to the cytoplasmic domains of these receptors. The phenotype of XLP may therefore result from perturbed signaling through SAP-associating receptors. We have addressed the functional consequence of SAP deficiency on 2B4-mediated NK cell activation. Ligating 2B4 on normal human NK cells with anti-2B4 mAb or interaction with transfectants bearing the 2B4 ligand CD48 induced NK cell cytotoxicity. In contrast, ligation of 2B4 on NK cells from a SAP-deficient XLP patient failed to initiate cytotoxicity. Despite this, CD2 or CD16-induced cytotoxicity of SAP-deficient NK cells was similar to that of normal NK cells. Thus, selective impairment of 2B4-mediated NK cell activation may contribute to the immunopathology of XLP.

Gntb-A, a Novel Sh2d1a-Associated Surface Molecule Contributing to the Inability of Natural Killer Cells to Kill Epstein-Barr Virus–Infected B Cells in X-Linked Lymphoproliferative Disease

“…These studies suggested a “lack of function” of 2B4 31 32. Further studies should clarify these divergent results and in particular whether they reflect a heterogeneity of the patients phenotype or other yet unknown mechanisms.…”

“…A dramatically altered function of 2B4 has recently been detected in individuals affected by the X-linked lymphoproliferative disease (XLP [28, 31, 32]). XLP is a severe inherited immune deficiency, characterized by the inability to control EBV infection resulting in fulminant infectious mononucleosis or lymphoma 33 34.…”

Homophilic interaction of NTBA, a member of the CD2 molecular family: induction of cytotoxicity and cytokine release in human NK cells

“…Moreover, in NK cells derived from these patients both CD244 and NTBA have been shown transduce abnormal inhibitory signals resulting in sharp inhibition of cytotoxicity against EBV-infected cells [1,[19][20][21]. This may contribute to the pathogenesis and to the progression of the disease since B-EBV-infected cells are characterized by high levels of expression of CD244-and NTBA-specific ligands, i.e.…”

“…Indeed, in the absence of SH2D1A molecule, the interaction of CD244 and NTBA with their ligands on EBVinfected cells has been shown to transduce inhibitory signals that render XLP-NK cells unable to kill EBVinfected targets [19][20][21]. While the ligand recognized by CD244, i.e.…”

Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus

“…The important role of 2B4 has been implicated in various infection and clinical settings. For example, a number of studies revealed that an inability to signal via 2B4 due to a genetic defect in SAP may contribute to the pathogenesis of XLP [25][26][27]. Human 2B4 expression is up-regulated on CD8 + T lymphocytes raised in response to herpes simplex virus (HSV), which lysed infected cells more efficiently [28].…”