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

Abstract

In humans, natural killer (NK) cell function is regulated by a series of receptors and coreceptors with either triggering or inhibitory activity. Here we describe a novel 60-kD glycoprotein, termed NTB-A, that is expressed by all human NK, T, and B lymphocytes. Monoclonal antibody (mAb)-mediated cross-linking of NTB-A results in the induction of NK-mediated cytotoxicity. Similar to 2B4 (CD244) functioning as a coreceptor in the NK cell activation, NTB-A also triggers cytolytic activity only in NK cells expressing high surface densities of natural cytotoxicity receptors. This suggests that also NTB-A may function as a coreceptor in the process of NK cell activation. Molecular cloning of the cDNA coding for NTB-A molecule revealed a novel member of the immunoglobulin superfamily belonging to the CD2 subfamily. NTB-A is characterized, in its extracellular portion, by a distal V-type and a proximal C2-type domain and by a cytoplasmic portion containing three tyrosine-based motifs. NTB-A undergoes tyrosine phosphorylation and associates with the Src homology 2 domain–containing protein (SH2D1A) as well as with SH2 domain–containing phosphatases (SHPs). Importantly, analysis of NK cells derived from patients with X-linked lymphoproliferative disease (XLP) showed that the lack of SH2D1A protein profoundly affects the function not only of 2B4 but also of NTB-A. Thus, in XLP-NK cells, NTB-A mediates inhibitory rather than activating signals. These inhibitory signals are induced by the interaction of NTB-A with still undefined ligands expressed on Epstein-Barr virus (EBV)-infected target cells. Moreover, mAb-mediated masking of NTB-A can partially revert this inhibitory effect while a maximal recovery of target cell lysis can be obtained when both 2B4 and NTB-A are simultaneously masked. Thus, the altered function of NTB-A appears to play an important role in the inability of XLP-NK cells to kill EBV-infected target cells.

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

“…The experiments were performed using polyclonal NK cells derived from either healthy donors or XLP patients. XLP-NK cells were previously shown to express NTBA molecules with inhibitory rather than activating function [1]. As shown in Fig.…”

“…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.…”

“…The NK92 cell line expresses NTBA, CD244, NKp30, NKp44, and NKG2D, but lacks the NKp46 receptor [1]. As shown in Fig.…”

“…NK-T-B antigen (NTBA) is a recently identified surface molecule expressed on NK, T, and B cells [1]. In human NK cells, NTBA has been shown to act primarily as a coreceptor since it could trigger cytolytic activity only in cells expressing high surface densities of natural cytotoxicity receptors (NCR) [2].…”

Increased proliferation of CD8+ T cells in SAP‐deficient mice is associated with impaired activation‐induced cell death

“…The adaptor SAP binds with high affinity to tyrosine motifs in the cytoplasmic domain of SLAM family immune receptors, including SLAM (CD150), CD244, CD229, SLAMF6, SLAMF7 and CD84, suggesting that SAP functions are important in modulating signals initiated by the SLAM family receptors [5][6][7][8]. It has been well established that SAP is an essential adaptor due to its capacity to recruit FynT to SLAM and p85 of PI3 K to 2B4, respectively [9,10].…”