Missing or altered self: human NK cell receptors that recognize HLA-C

Abstract

Natural killer (NK) cells are fast-acting and versatile lymphocytes that are critical for innate immunity, adaptive immunity and placental development. Controlling NK cell function are interactions between killer-cell immunoglobulin-like receptors (KIRs) and their HLA-A, -B and -C ligands. Due to the extensive polymorphism of both KIR and HLA class I, these interactions are highly diversified and specific combinations correlate with protection or susceptibility to a range of infectious, autoimmune and reproductive disorders. Evolutionary, genetic and functional studies are consistent with the interactions between KIR and HLA-C being the dominant control mechanism of human NK cells. In addition to their recognition of the C1 and C2 epitopes, increasing evidence points to KIR having a previously unrecognized selectivity for the peptide presented by HLA-C. This selectivity appears to be a conserved feature of activating KIR and may partly explain the slow progress made in identifying their HLA class I ligands. The peptide selectivity of KIR allows NK cells to respond, not only to changes in the surface expression of HLA-C, but also to the more subtle changes in the HLA-C peptidome, such as occur during viral infection and malignant transformation. Here we review recent advances in understanding of human-specific KIR evolution and how the inhibitory and activating HLA-C receptors allow NK cells to respond to healthy cells, diseased cells and the semi-allogeneic cells of the fetus.

A novel antibody combination to identify KIR2DS2high natural killer cells in KIR2DL3/L2/S2 heterozygous donors

“…The killer cell immunoglobulin‐like receptors (KIRs) are expressed by NK cells as well as subsets of T cells and recognise the combination of HLA‐C with bound peptide. The specificity of inhibitory KIRs have been well documented, as they detect HLA‐C downregulation and are also modulated by changes in the peptide content of HLA‐C . In contrast, much less is known about the activating KIR, although they have been shown to play a significant role in viral infections and cancer .…”

“…1,2 The killer cell immunoglobulin-like receptors (KIRs) are expressed by NK cells as well as subsets of T cells and recognise the combination of HLA-C with bound peptide. The specificity of inhibitory KIRs have been well documented, as they detect HLA-C downregulation and are also modulated by changes in the peptide content of HLA-C. [3][4][5] In contrast, much less is known about the activating KIR, although they have been shown to play a significant role in viral infections and cancer. [6][7][8][9] The activating KIR, KIR2DS2, is of particular interest given its protective role in bone marrow and cord blood transplantation for various hematological malignancies 10,11 and in glioblastoma models in vivo.…”

Molecular evolution of elements controlling HLA‐C expression: Adaptation to a role as a killer‐cell immunoglobulin‐like receptor ligand regulating natural killer cell function

“…11,12 The hypothesis that HLA-C has evolved to serve as a specialized MHC class I gene and function primarily as a KIR ligand is supported by several lines of evidence: (a) HLA-C is the most recently evolved MHC class I gene, resulting from the duplication and divergence of the HLA-B gene 13 , (b) The emergence and divergence of HLA-C correlates with the expansion of the family of KIR receptors that recognize it, 14 (c) all HLA-C alleles serve as ligands for at least one KIR, whereas only HLA-A and HLA-B alleles that contain the Bw4 epitope are recognized by KIR3DL1. Natural killer (NK) cells are less dependent on the recognition of Bw4, because approximately 50% of the world population possesses Bw4 epitopes in their genome, 15 (d) the level of cell surface expression of HLA-C is less than 10% of HLA-A or HLA-B levels, 16,17 which is more consistent with a role as a sensor for altered/downregulated class I in infected or transformed cells, rather than presentation of peptides to T cells, 18 (e) the recent identification of an NK-specific upstream HLA-C promoter that is associated with increased HLA-C expression by NK cells, 19 indicates the importance of HLA-C for the development and regulation of NK cells.…”

Endoplasmic reticulum aminopeptidase 1 polymorphism Ile276Met is associated with atopic dermatitis and affects the generation of an HLA‐C associated antigenic epitope in vitro

“…3 NK cell function has been found to be affected by HLA class I-bound peptides. [4][5][6] The repertoire of these peptides is dependent on the activity of endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and 2), which are polymorphic elements of antigen-presenting machinery. [7][8][9] Therefore, we examined several single nucleotide polymorphisms (SNPs) of the ERAP1 and ERAP2 genes, potentially affecting enzyme activity or expression 10 in patients with AD and healthy control individuals.…”