Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients

Abstract

X-linked lymphoproliferative disease 1 (XLP1) is an inherited immunodeficiency, caused by mutations in SH2D1A encoding Signaling Lymphocyte Activation Molecule (SLAM)-associated protein (SAP). In XLP1, 2B4, upon engagement with CD48, has inhibitory instead of activating function. This causes a selective inability of cytotoxic effectors to kill EBV-infected cells, with dramatic clinical sequelae. Here, we investigated the NK cell education in XLP1, upon characterization of killer Ig-like receptor (KIR)/KIR-L genotype and phenotypic repertoire of self-HLA class I specific inhibitory NK receptors (self-iNKRs). We also analyzed NK-cell cytotoxicity against CD48 or CD48 KIR-ligand matched or autologous hematopoietic cells in XLP1 patients and healthy controls. XLP1 NK cells may show a defective phenotypic repertoire with substantial proportion of cells lacking self-iNKR. These NK cells are cytotoxic and the inhibitory 2B4/CD48 pathway plays a major role to prevent killing of CD48 EBV-transformed B cells and M1 macrophages. Importantly, self-iNKR defective NK cells kill CD48 targets, such as mature DCs. Self-iNKR NK cells in XLP1 patients are functional even in resting conditions, suggesting a role of the inhibitory 2B4/CD48 pathway in the education process during NK-cell maturation. Killing of autologous mature DC by self-iNKR defective XLP1 NK cells may impair adaptive responses, further exacerbating the patients' immune defect.

Killer‐cell immunoglobulin‐like receptors on the cusp of modern immunogenetics

“…In this session chaired by Jens Kieckbusch, Daniela Pende showed that NK cells from patients with X‐linked lymphoproliferative disease have a defective phenotypic repertoire with a substantial proportion of the cells lacking self HLA class I specific inhibitory receptors compared with healthy controls . Their results showed that, in patients with X‐linked lymphoproliferative disease, the inhibitory 2B4/CD48 pathway contributes to NK cell education and could play a role in preventing killing of CD48 + Epstein–Barr virus‐infected cells.…”

The Broad Spectrum of Human Natural Killer Cell Diversity

“…This represents an unexpectedly large number of theoretically uneducated NK cells and would at first glance seem like a high amount of inefficiency in how the body produces effector NK cells. However, recent studies in both mice and humans indicate that other receptors, such as the SLAM family receptors 2B4 and SLAMF6, can also mediate NK cell education in addition to KIRs and CD94/NKG2A (Chen et al, 2016a; He and Tian, 2017; Meazza et al, 2017; Wu et al, 2016). Furthermore, there is also recent evidence that educated and uneducated NK cells can serve distinct roles in the body, with educated NK cells providing immunity against MHC-deficient tumors and uneducated NK cells providing immunity against some viral infections and tumors that retain MHC expression (Orr et al, 2010; Tu et al, 2016; Zamora et al, 2017).…”

Killer Ig-Like Receptors (KIRs): Their Role in NK Cell Modulation and Developments Leading to Their Clinical Exploitation

“…This specific immune dysfunction in XLP1 patients causes the inability of NK cells to kill EBV-infected B cells (B-EBV), over-expressing their ligands (i.e., CD48 and NTB-A), with dramatic clinical consequences. Following this knowledge, we further analyzed the NK cell receptor repertoire of these patients, showing that substantial proportions of NK cells lacking any inhibitory receptor specific for self-HLA (self-NKR neg ) are present and are fully functional, indicating that inhibitory 2B4 participates to NK cell education (177). Remarkably, self-NKR neg NK cells can efficiently kill CD48 neg target cells, such as mature DC, with consequently defective antigen presentation, further exacerbating the immune defect of these patients.…”