The Intergenic Recombinant HLA-B∗46:01 Has a Distinctive Peptidome that Includes KIR2DL3 Ligands

Hilton, Hugo G.; McMurtrey, Curtis P.; Han, Alex S.; Djaoud, Zakia; Guethlein, Lisbeth A.; Blokhuis, Jeroen H.; Pugh, Jason L.; Goyos, Ana; Horowitz, Amir; Buchli, Rico; Jackson, Ken W.; Bardet, Wilfried; Bushnell, David; Robinson, Philip J.; Mendoza, Juan L.; Birnbaum, Michael E.; Nielsen, Morten; García, K. Christopher; Hildebrand, William H.; Parham, Peter

doi:10.1016/j.celrep.2017.04.059

Cited by 41 publications

(43 citation statements)

References 78 publications

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“…Hugo Hilton presented his high resolution mass spectrometry peptide analysis of the intergenic recombinant HLA-B*46:01, showing that its recent increase in South-East Asia may relate to its ability to provide ligands for C1-specific KIR and its distinctive peptide repertoire. 6 Malcolm Sim showed that KIR2DL3 binding to HLA-C1 was more peptide-dependent than KIR2DL1 binding to C2, providing a possible explanation for why KIR2DL3-C1 interactions appear weaker than KIR2DL1-C2 interactions. 7 The peptide selectivity of KIR2DL3-C1 interactions may be important in cancer cell recognition because the peptides in the cancer cell may differ from those that shape NK cell education in resting state.…”

Section: Kir Structure and Peptidesmentioning

confidence: 99%

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

Colucci

Traherne

2017

Immunology

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SummaryKiller-cell immunoglobulin-like receptors (KIR) and their human leukocyte antigen (HLA) ligands play a central role in immunity and human health. These molecules are encoded by gene families with copy number variation, extreme levels of sequence diversity and complex expression patterns. The rapid evolution of KIR and HLA genes and their associations with infectious diseases, pregnancy disorders, immunopathologies and outcome of cell transplantation have generated considerable interest from immunologists, geneticists and clinicians. Until recently, however, analyses have been stuck at low-level resolution, focusing primarily on presence or absence of KIR genes. This is changing with the advent of modern high throughput sequencing, cell phenotyping and bioinformatics. These developments allow high-resolution analysis and much deeper understanding of KIR evolution and KIR function. The impending deluge of high dimensional data brings inevitably new challenges in analysis, interpretation and communication of results, but the benefits are already tangible. The diversity of KIR across worldwide human populations is being catalogued at the allele level. Structures of KIR molecules and their interactions with HLA-peptide complexes are being determined. How KIR modulate natural killer cell education is being defined. Ligands for activating KIR, elusive for many years, are being discovered. KIR gene complexes and their related receptor gene families are being characterized in animal models and livestock breeds. These advances are helping to generate a more complete picture of the impact of KIR variation in health and disease and offer new opportunities for immunotherapy, as highlighted in a recent meeting (The Tenth KIR Workshop, April 2017 Cambridge, UK).

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Section: Kir Structure and Peptidesmentioning

confidence: 99%

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

Colucci

Traherne

2017

Immunology

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“…Consistent with the structural picture, KIR2DL2/3 shows greater peptide selectivity than KIR2DL1 (Sim et al 2017). Supporting this finding, our examination of endogenously processed peptides from C1 + HLA-C and HLA-B showed that <25% of the peptides are strong KIR2DL3 ligands (Hilton et al 2017b). The peptide selectivity of KIR2DL2/3 was further highlighted by the observation that peptide positions other than P7 and P8 have potential to influence the recognition of C1 + HLA-C (Hilton et al 2017b; Sim et al 2017).…”

Section: Introductionmentioning

confidence: 72%

“…Supporting this finding, our examination of endogenously processed peptides from C1 + HLA-C and HLA-B showed that <25% of the peptides are strong KIR2DL3 ligands (Hilton et al 2017b). The peptide selectivity of KIR2DL2/3 was further highlighted by the observation that peptide positions other than P7 and P8 have potential to influence the recognition of C1 + HLA-C (Hilton et al 2017b; Sim et al 2017). That KIR2DL3 appears as the receptor with the most peptide selectivity provides a compelling rationale for the observation that KIR2DL3 binding to C1 + HLA-C is weaker than KIR2DL1 binding to C2 + HLA-C (Moesta et al 2008).…”

Section: Introductionmentioning

confidence: 72%

“…The two mutually exclusive HLA-C epitopes are defined by dimorphism at positon 80 in the α 1 helix. The HLA-C1 epitope is defined by N80 and recognized by KIR with K44 (KIR2DL2/3, K44-KIR2DP1 F , KIR2DS2), the HLA-C2 epitope is defined by K80 and recognized by KIR with either M44 (KIR2DL1, KIR2DS1) or T44 (KIR2DS3/5, T44-KIR2DP1 F ) (Hilton et al 2017b; Moesta et al 2008; Moesta et al 2010; Winter et al 1998). …”

Section: Introductionmentioning

confidence: 99%

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

Hilton

Parham

2017

Immunogenetics

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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.

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“…Allelic variants predominantly differ by single nucleotide polymorphisms (SNPs) or insertion/deletions (indels), however, novel alleles can be generated by homologous recombination mechanisms. Recombination can involve alleles at the same locus (ie, intra‐locus recombination for example, HLA‐B*50:51 derived from HLA‐B*50:01:01:02 and HLA‐B*14:02:01 ) or alleles at different loci (ie, inter‐locus recombination for example, HLA‐B*46:01 derived from HLA‐B*15:01 and HLA‐C*01:02 ).…”

Section: New Allele Alertmentioning

confidence: 99%