Activating Receptors and Coreceptors Involved in Human Natural Killer Cell-Mediated Cytolysis

Abstract

Natural killer cells can discriminate between normal cells and cells that do not express adequate amounts of major histocompatibility complex (MHC) class I molecules. The discovery, both in mouse and in human, of MHC-specific inhibitory receptors clarified the molecular basis of this important NK cell function. However, the triggering receptors responsible for positive NK cell stimulation remained elusive until recently. Some of these receptors have now been identified in humans, thus shedding some light on the molecular mechanisms involved in NK cell activation during the process of natural cytotoxicity. Three novel, NK-specific, triggering surface molecules (NKp46, NKp30, and NKp44) have been identified. They represent the first members of a novel emerging group of receptors collectively termed natural cytotoxicity receptors (NCR). Monoclonal antibodies (mAbs) to NCR block to differing extents the NK-mediated lysis of various tumors. Moreover, lysis of certain tumors can be virtually abrogated by the simultaneous masking of the three NCRs. There is a coordinated surface expression of the three NCRs, their surface density varying in different individuals and also in the NK cells isolated from a given individual. A direct correlation exists between the surface density of NCR and the ability of NK cells to kill various tumors. NKp46 is the only NCR involved in human NK-mediated killing of murine target cells. Accordingly, a homologue of NKp46 has been detected in mouse. Molecular cloning of NCR revealed novel members of the Ig superfamily displaying a low degree of similarity to each other and to known human molecules. NCRs are coupled to different signal transducing adaptor proteins, including CD3 zeta, Fc epsilon RI gamma, and KARAP/DAP12. Another triggering NK receptor is NKG2D. It appears to play either a complementary or a synergistic role with NCRs. Thus, the triggering of NK cells in the process of tumor cell lysis may often depend on the concerted action of NCR and NKG2D. In some instances, however, it may uniquely depend upon the activity of NCR or NKG2D only. Strict NKG2D-dependency can be appreciated using clones that, in spite of their NCR(dull) phenotype, efficiently lyse certain epithelial tumors or leukemic cell lines. Other triggering surface molecules including 2B4 and the novel NKp80 appear to function as coreceptors rather than as true receptors. Indeed, they can induce natural cytotoxicity only when co-engaged with a triggering receptor. While an altered expression or function of NCR or NKG2D is being explored as a possible cause of immunological disorders, 2B4 dysfunction has already been associated with a severe form of immunodeficiency. Indeed, in patients with the X-linked lymphoproliferative disease, the inability to control Epstein-Barr virus infections may be consequent to a major dysfunction of 2B4 that exerts inhibitory instead of activating functions.

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

“…2B4 has been shown to associate with SHP-1 and, upon sodium pervanadate treatment or mAb-mediated cross-linking, with SH2D1A 27 28 29. On the other hand, IRp60 is an immune tyrosine-based inhibitory motif (ITIM)-bearing receptor that associates with both SHP-1 and SHP-2 39, while NKp46, lacking tyrosine-based motifs in the cytoplasmic tail, transduces the activating signals via the association with CD3ζ and FcεRIγ ITAM-containing transmembrane adaptor molecules 4. This analysis revealed the presence of SHP-1 in NTB-A immunoprecipitates obtained from both untreated and sodium pervanadate–treated cells.…”

“…Some of these receptors inhibit NK cells by monitoring the expression of MHC class I molecules on normal cells 1 2 3. Other receptors are responsible for NK cell activation 4. This occurs when NK cells interact with cells that, as a consequence of viral infection or tumor transformation, do not express, or express inadequate amounts of, MHC class I molecules 5.…”

Nidogen-1 is a novel extracellular ligand for the NKp44 activating receptor

“…1-9 In order to fulfill this variety of functions, NK cells use an array of receptors which sense microenvironmental stimuli and mediate appropriate responses. 3,10,11 Several NK receptors are capable of regulating different NK cell functions. For example, the Natural Cytotoxicity Receptors (NCRs) NKp46, NKp30, and NKp44, play an important role in human NK cell-mediated recognition and killing of virally infected and tumor cells, and also induce the release of a number of cytokines and chemotactic factors.…”

“…For example, the Natural Cytotoxicity Receptors (NCRs) NKp46, NKp30, and NKp44, play an important role in human NK cell-mediated recognition and killing of virally infected and tumor cells, and also induce the release of a number of cytokines and chemotactic factors. 10,12 In addition, NKp30 and NKp46 mediate regulatory interactions occurring between NK and different leukocytes, including dendritic cells (DCs), neutrophils, eosinophils, macrophages, and T cells. 5-9 NCRs were identified and molecularly characterized in ‘90s.…”

“…16-21 In spite of many efforts, so far, the panel of the NCR ligands has been only partially defined. 10,12,22 A reason of these difficulties is related to the fact that study models of receptor-ligand interaction for the NCR are rather limited, as only NKp46 is expressed also on NK cells of rat and mouse. Moreover, although the NCRs belong to the Ig superfamily, they greatly differ in their molecular structure, implying that their ligands may be rather heterogeneous.…”