Peptide selectivity discriminates NK cells from KIR2DL2‐ and KIR2DL3‐positive individuals

Cassidy, Sorcha; Mukherjee, Sayak; Myint, Thet Mon; Mbiribindi, Bérénice; North, Helen; Traherne, James A.; Mulder, Arend; Claas, Frans H.J.; Purbhoo, Marco A.; Das, Jayajit; Khakoo, Salim I.

doi:10.1002/eji.201444613

Cited by 25 publications

(23 citation statements)

References 32 publications

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“…This indicates that the increase in degranulation was related either to KIR2DL2 or to KIR2DS2. KIR2DL2 + NK cells are less responsive to changes in peptide content of MHC class I than KIR2DL3 + NK cells (19). Therefore, we reasoned that this change in degranulation was related to NK cell activation through engagement of KIR2DS2.…”

Section: Kir2ds2 Recognizes the Hcv Peptide Lnpsvaatl In The Context mentioning

confidence: 96%

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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Section: Kir2ds2 Recognizes the Hcv Peptide Lnpsvaatl In The Context mentioning

confidence: 96%

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

et al. 2017

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“…Recent studies point to differences in peptide selectivity within the various inhibitory KIR that recognize HLA-C (Cassidy et al 2015; Sim et al 2017). Consistent with the structural picture, KIR2DL2/3 shows greater peptide selectivity than KIR2DL1 (Sim et al 2017).…”

Section: Introductionmentioning

confidence: 99%

“…A key discovery from such studies was that some weak KIR ligands compete effectively with strong KIR ligands. This phenomenon is termed peptide antagonism (Cassidy et al 2015; Fadda et al 2010). Such competition reduces KIR-mediated inhibition (Borhis et al 2013; Fadda et al 2010) to favor target cell lysis.…”

Section: Introductionmentioning

confidence: 99%

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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“…Indeed peptides have been shown to influence the specificity of particular KIR-HLA ligand interactions (48). Unfortunately, the associative nature of our study falls short in providing precise mechanistic insights of how the KIR2DS4 Ã 00101-HLA-C1/C2 interactions may be contributing to the immune regulation in glioblastoma patients.…”

Section: Discussionmentioning

confidence: 94%

Identification of a Natural Killer Cell Receptor Allele That Prolongs Survival of Cytomegalovirus-Positive Glioblastoma Patients

et al. 2016

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By affecting immunological presentation, the presence of cytomegalovirus in some glioblastomas may impact progression. In this study, we examined a hypothesized role for natural killer (NK) cells in impacting disease progression in this setting. We characterized 108 glioblastoma patients and 454 healthy controls for HLA-A,-B,-C, NK-cell KIR receptors, and CMV-specific antibodies and correlated these metrics with clinical parameters. Exome sequences from a large validation set of glioblastoma patients and control individuals were examined from in silico databases. We demonstrated that the KIR allele KIR2DS4 Ã 00101 was independently prognostic of prolonged survival. KIR2DS4Ã 00101 displayed 100% concordance with cognate HLA-C1 ligands in glioblastoma patients, but not controls. In the context of both HLA-C1/C2 ligands for the KIR2DS4 receptor, patient survival was further extended. Notably, all patients carrying KIR2DS4Ã 00101 alleles were CMV seropositive, but not control individuals, and exhibited increased NK-cell subpopulations, which expressed the cytotoxicity receptors CD16, NKG2D, and CD94/NKG2C. Finally, healthy controls exhibited a reduced risk for developing glioblastoma if they carried two KIR2DS4

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Peptide selectivity discriminates NK cells from KIR2DL2‐ and KIR2DL3‐positive individuals

Cited by 25 publications

References 32 publications

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

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

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

Identification of a Natural Killer Cell Receptor Allele That Prolongs Survival of Cytomegalovirus-Positive Glioblastoma Patients

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