Structure/function of human killer cell immunoglobulin-like receptors: Lessons from polymorphisms, evolution, crystal structures and mutations

Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Immunology (Impact Factor: 3.8). 03/2011; 132(3):315-25. DOI: 10.1111/j.1365-2567.2010.03398.x
Source: PubMed


Stimulation or tolerance of natural killer (NK) cells is achieved through a cross-talk of signals derived from cell surface activating and inhibitory receptors. Killer cell immunoglobulin-like receptors (KIR) are a family of highly polymorphic activating and inhibitory receptors that serve as key regulators of human NK cell function. Distinct structural domains in different KIR family members determine function by providing docking sites for ligands or signalling proteins. Here, we review a growing body of literature that has identified important structural elements on KIR that contribute to function through studies of engineered mutants, natural polymorphic sequence variants, crystal structure data and the conservation of protein sequences throughout primate evolution. Extensive natural polymorphism is associated with both human KIR and their ligands, MHC class I (HLA-A, -B and -C) molecules, and numerous studies have demonstrated associations between inheritance of certain combinations of KIR and HLA genes and susceptibility to several diseases, including viral infections, autoimmune disorders and cancers. In addition, certain KIR/HLA combinations can influence pregnancy and the outcome of haematopoietic stem cell transplantation. In view of the significant regulatory influences of KIR on immune function and human health, it is essential to fully understand the impacts of these polymorphic sequence variations on ligand recognition, expression and function of the receptor.

Download full-text


Available from: Kerry S Campbell
  • Source
    • "Phosphatase recruitment further leads to Vav dephosphorylation and the subsequent disruption of activation signals (Figure 1) (17). The role of SH2-containing phosphatases in NK-cell licensing and function has also been the subject of investigation (40, 41). However, results from these studies have been difficult to interpret. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Natural killer (NK) cells provide essential protection against viral infections. One of the defining features of this lymphocyte population is the expression of a wide array of variable cell surface stimulatory and inhibitory NK receptors (sNKR and iNKR, respectively). The iNKR are particularly important in terms of NK-cell education. As receptors specific for MHC class I (MHC I) molecules, they are responsible for self-tolerance and adjusting NK-cell reactivity based on the expression level of self-MHC I. The end result of this education is twofold: (1) inhibitory signaling tunes the functional capacity of the NK cell, endowing greater potency with greater education, and (2) education on self allows the NK cell to detect aberrations in MHC I expression, a common occurrence during many viral infections. Many studies have indicated an important role for iNKR and MHC I in disease, making these receptors attractive targets for manipulating NK-cell reactivity in the clinic. A greater understanding of iNKR and their ability to regulate NK cells will provide a basis for future attempts at translating their potential utility into benefits for human health.
    Full-text · Article · Apr 2014 · Frontiers in Immunology
  • Source
    • "Thus, cells that evade cytotoxic CD8+ T-cell recognition and killing by downmodulating the expression of MHC1, render themselves potential targets for NK cell mediated elimination. In addition, several other inhibitory receptors, which bind to non-MHC1 ligands exist, including CEACAM1, CD300a, and TIGIT (26–31). All the different inhibitory receptors contain one or more intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs), which mediate the downstream inhibitory signals by recruiting protein tyrosine phosphatases (32). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Natural killer (NK) cells are innate immune lymphocytes that function mainly as immune sentinels against viral infection and tumorigenesis. NK cell function is governed by inhibitory and activating signals arising from corresponding receptors. A prominent group of activating NK receptors is the natural cytotoxicity receptors (NCRs), which includes NKp30, NKp44, and NKp46. These receptors bind various diverse ligands of pathogenic, tumor, and even self origin. Type 1 diabetes mellitus (T1D) is a multifactorial autoimmune disease, in which insulin-producing beta (β) cells are ablated by the immune system. This killing of β cells is carried out mainly by T cells, but many other immune cells have been implicated in the pathogenesis of this disease. Importantly, NK cells were shown to be key participants in the initial autoimmune attack. It was shown that all β cells from humans and mice, healthy or sick, express an unknown ligand for the activating NKp46 receptor. In this review, we describe the role played by the NCRs in various pathologies with an emphasis on Type I diabetes.
    Full-text · Article · Jan 2014 · Frontiers in Immunology
  • Source
    • "In humans, proline 11 and threonine 13 are uniquely located and conserved within the transmembrane domains of activating KIRs [25]. Modifications at these residues have been shown to diminish association with DAP12 [25,26]. Since A. vociferans short cytoplasmatic tail receptors had these amino acids conserved at the same position (Figure 1), association between these AOTVOKIRs and adapter molecules might be facilitated by proline and theronine residues. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Previous BAC clone analysis of the Platyrrhini owl monkey KIRs have shown an unusual genetic structure in some loci. Therefore, cDNAs encoding KIR molecules from eleven Aotus vociferans monkeys were characterized here; ten putative KIR loci were found, some of which encoded atypical proteins such as KIR4DL and transcripts predicted to encode a D0+D1 configuration (AOTVOKIR2DL1*01v1) which appear to be unique in the Aotus genus. Furthermore, alternative splicing was found as a likely mechanism for producing activator receptors in A. vociferans species. KIR proteins from New World monkeys may be split into three new lineages according to domain by domain phylogenetic analysis. Although the A. vociferans KIR family displayed a high divergence among paralogous genes, individual loci were limited in their genetic polymorphism. Selection analysis showed that both constrained and rapid evolution may operate within the AvKIR family. The frequent alternative splicing (as a likely mechanism generating activator receptors), the presence of KIR4DL and KIR2DL1 (D0+D1) molecules and other data reported here suggest that the KIR family in Aotus has had a rapid evolution, independent from its Catarrhini counterparts.
    Full-text · Article · Nov 2013 · PLoS ONE
Show more