Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C

Sim, Malcolm J. W.; Malaker, Stacy A.; Khan, Ayesha; Stowell, Janet; Shabanowitz, Jeffrey; Peterson, Mary; Rajagopalan, Sumati; Hunt, Donald F.; Altmann, Daniel M.; Long, Eric O.; Boyton, Rosemary J.

doi:10.1101/096958

Cited by 17 publications

(52 citation statements)

References 58 publications

(104 reference statements)

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“…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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“…KIR2DL2 and KIR2DL3 are inhibitory KIRs with a predominant specificity for the group 1 HLA-C allotypes (HLA-C1). Both these inhibitory receptors have similar specificities for peptide:MHC, as could be predicted from the high sequence homology of their extra-cellular domains (10).…”

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confidence: 87%

KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C

et al. 2017

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This is the author accepted manuscript (AAM). The final published version (version of record) is available online via AAAS at http://immunology.sciencemag.org/content/2/15/eaal5296. Please refer to any applicable terms of use of the publisher. University of Bristol -Explore Bristol Research General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. KIR2DS2, an activating natural killer cell receptor recognizes highly conserved peptides derived from the RNA helicases of pathogenic flaviviruses. AbstractKiller cell immunoglobulin-like receptors (KIR) are rapidly evolving species-specific natural killer cell receptors associated with protection against multiple different human viral infections. We report that the activating receptor KIR2DS2 directly recognizes viral peptides derived from conserved regions of flaviviral superfamily 2 RNA helicases in the context of MHC class I. The peptide LNPSVAATL, from the HCV helicase, binds HLA-C*0102 leading to NK cell activation through engagement of KIR2DS2. Similarly, HLA-C*0102 presents highly conserved peptides from the helicase motif 1b region of related flaviviruses, including dengue, Zika, yellow fever and Japanese encephalitis viruses, to KIR2DS2. These flaviviral peptides all contain an "MCHAT" motif, which is present in 61 out of 63 flaviviruses.LNPSVAATL is also highly conserved across HCV genotypes and mutation of this epitope is poorly tolerated by HCV. KIR2DS2 recognizes endogenously presented helicase peptides and KIR2DS2 is sufficient to inhibit HCV and dengue virus replication in the context of HLA-C*0102. Targeting short, but highly conserved, viral peptides provide non-rearranging innate immune receptors with an efficient mechanism to recognize multiple, highly variable pathogenic RNA viruses.4

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“…Binding of activating KIRs to HLA class I is influenced by HLA-bound peptides. [4][5][6] Since ERAP1 is primarily a MHC-I cargo optimizer, one could hypothesize that a 'slower' allele limits optimal peptide cargo, allowing for less optimal peptides to be bound and presented, eliciting cytotoxic responses. KIR2DS1 might enable NK cells to kill effectors of AD independently of ERAP1-provided peptide, whereas, in the absence of this KIR, the activity of CD8 + T cells contributing to AD might be influenced by an HLA-C*05:01presented peptide produced by ERAP1 more or less efficiently depending on its rs26618 variant.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Niepiekło-Miniewska

Mpakali

Stratikos

et al. 2019

Acad Dermatol Venereol

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Background Atopic dermatitis (AD) is a common inflammatory skin disease of complex aetiology, with interactions between susceptibility genes and environmental factors. We have previously described a protective effect of the KIR2DS1 gene encoding the natural killer cell receptor, whose ligands are HLA-C molecules. Here, we found an association of HLA-C*05:01 allele with AD. KIR-HLA-C interactions are affected by peptides presented by HLA-C. The generation of these peptides is strongly influenced by endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2).Expression and activity of ERAP molecules depend on the polymorphisms of their genes.Objective Possible associations of several single nucleotide polymorphisms (SNPs) in the ERAP1 and ERAP2 genes with susceptibility to AD.Methods Peripheral blood DNA isolation from 318 patients and 549 controls. PCR-SSO or PCR-SSP for HLA-C typing;TaqMan Genotyping Assay for ERAP typing.Results Only one SNP in the ERAP1 gene, rs26618T>C, causing the amino acid change Ile276Met, had an association with AD. To gain insight on the functional role of this SNP, we produced recombinant variants differing only at position 276 (Ile or Met) and tested their aminopeptidase activity against a N-terminally extended precursor LIVDRPVTLV of the HLA-C*05:01 epitope IVDRPVTLV. Both ERAP1 variants were able to efficiently generate the epitope, although the 276Ile allotype was able to do this about 50% faster. Furthermore, both variants were quite inefficient in further degradation of the mature epitope. Finally, we found that the effect of 276Met on susceptibility to AD was seen only in KIR2DS1negative individuals, not protected by this KIR.Conclusion Associations of HLA-C*05:01 allele and rs26618T>C (Ile276Met) ERAP1 polymorphism with AD, and a significant difference between these two ERAP1 variants in their ability to generate an epitope for the HLA-C*05:01 molecule was found.

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Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C

Cited by 17 publications

References 58 publications

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

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

KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C

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

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