Functional Polymorphism of the KIR3DL1/S1 Receptor on Human NK Cells

O’Connor, Geraldine M.; Guinan, Kieran J.; Cunningham, Rodat T.; Middleton, Derek; Parham, Peter; Gardiner, Clair M.

doi:10.4049/jimmunol.178.1.235

Cited by 148 publications

(151 citation statements)

References 28 publications

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“…Several studies have shown that HLA-Bw4 is a strong inhibitory ligand for 3DL1 on NK cells. 14,39 Overall, this indicates that NK cell-responsive phenotypes in north-northwestern Europe are increased in frequency as a consequence of the predominance of the relatively weak 2DL3:HLA-C1 inhibitory system, whereas this phenotype is lower in frequency in the south of Europe because of the increase prevalence of the more potent HLA-C2 and HLA-B-Bw4 inhibitory system. This finding is significant as it shows genetic stratification of epistatic KIR:HLA receptor systems, which allow 'functional gradients' likely to affect human immunity, in different European populations to be defined.…”

Section: Discussionmentioning

confidence: 95%

Receptor systems controlling natural killer cell function are genetically stratified in Europe

et al. 2009

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Natural killer (NK) cells are components of the innate immune system that function in identifying and destroying aberrant or pathogen-infected cells. These functions are largely controlled by killer cell immunoglobulin-like receptors (KIRs). KIRs inhibit and activate NK cell functions through interactions with their ligands, epitopes encoded by human leukocyte antigen (HLA) class I genes (HLA-C1, C2 and Bw4). Genes that encode KIR and their HLA ligands vary in frequency across human populations. Here, we characterize two Irish populations for KIR and HLA and determine the spatial distribution of functionally important KIR:HLA systems in Europe, a region known for its considerable underlying genetic stratification. We find that Southern Europe is a region characterized by higher frequencies of activatory KIR and strong inhibitory HLA ligand systems (2DL1:HLA-C2 and 3DL1:Bw4). A lower frequency of activatory KIR and the predominance of a comparatively weaker inhibitory ligand system (2DL3:HLA-C1) are observed northwards. Despite contrasting KIR:HLA systems in Northern and Southern Europe, there is a clear balance between inhibitory and activatory repertoires, and their ligands in both regions. These findings show 'functional stratification' of the epistatic KIR:HLA receptor system in Europe, the presence of which will likely affect NK cell-mediated immunity across different populations.

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Section: Discussionmentioning

confidence: 95%

Receptor systems controlling natural killer cell function are genetically stratified in Europe

et al. 2009

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“…NK cells from donors no. 001 and 016 were tested with mAbs DX9 and Z27 (14,15). We were unable to identify a KIR3DS1-positive subset in either of these donors (data not shown).…”

Section: Freshly Isolated Nk Cells From 2ds1-positive C1 Group Homozmentioning

confidence: 92%

“…Therefore, the inhibitory pathway appears to dominate the activating pathway, thereby preventing NK-mediated autoreactivity. The activating KIR gene 3DS1 has recently been reported to encode an activating receptor (14,15), but no ligand specificity for the HLA-KIR ligand group Bw4 could be detected (15). The activating KIRs 2DS1, 2DS2, and 3DS1 are all associated with DAP12, which participates in the signaling events (9,15,16).…”

Section: A Ctivation Of Nk Cells Is Tightly Regulated By Multiple Inhmentioning

confidence: 99%

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KIR2DS1-Positive NK Cells Mediate Alloresponse against the C2 HLA-KIR Ligand Group In Vitro

Chewning

Gudme

Hsu

et al. 2007

The Journal of Immunology

169

147

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The inhibitory 2DL1 and activating 2DS1 killer Ig-like receptors (KIR) both have shared ligand specificity for codon sequences in the C2 group HLA-Cw Ags. In this study, we have investigated NK cell activation by allogeneic target cells expressing different combinations of the HLA-KIR ligand groups C1, C2, and Bw4. We demonstrate that fresh NK cells as well as IL-2-propagated NK cells from 2DS1-positive donors that are homozygous for the C1 ligand group are activated in vitro by B lymphoblastoid cell lines expressing the C2 group. This response is, in part, due to the absence of C1 group recognition mediated by the inhibitory receptor 2DL2/3. This “missing self” alloresponse to C2, however, is rarely observed in NK cells from donors lacking 2DS1. Even in presence of 2DS1, the NK alloresponse is dramatically reduced in donors that have C2 group as “self.” Analysis of selected NK clones that express 2DS1 mRNA and lack mRNA for 2DL1 demonstrates that activation by the C2 ligand and mAb cross-linking of 2DS1 in these clones induces IFN-γ. Furthermore, this C2 group-induced activation is inhibited by Abs to both HLA class I and the receptor. Collectively, these studies demonstrate that NK cells from 2DS1-positive donors are activated by target cells that express the C2 group as an alloantigen. This leads to increased IFN-γ-positive fresh NK cells and induces NK allocytotoxicity in IL2-propagated polyclonal NK cells and NK clones. This study also provides support for the concept that incompatibility for the HLA-KIR ligand groups C1, C2, and Bw4 dominates NK alloactivation in vitro.

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“…From this, testable hypotheses can be formed about the extent to which each gene or allele, in conjunction with ligand variation, can predispose to a phenotype. For example, the cell surface expression of KIR3DL1 and the ability to recognize HLA‐Bw4 ligand vary according to allele, and hence KIR3DL1 alleles should be analysed accordingly in the disease context 25, 38, 58, 72. Similarly, polymorphism in the extracellular domain of KIR2DL1 influences the binding affinity to HLA‐C2 34, 40.…”

Section: Kir Geneticsmentioning

confidence: 99%

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

et al. 2016

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SummaryKiller‐cell immunoglobulin‐like receptors (KIRs) are components of two fundamental biological systems essential for human health and survival. First, they contribute to host immune responses, both innate and adaptive, through their expression by natural killer cells and T cells. Second, KIR play a key role in regulating placentation, and hence reproductive success. Analogous to the diversity of their human leucocyte antigen class I ligands, KIR are extremely polymorphic. In this review, we describe recent developments, fuelled by methodological advances, that are helping to decipher the KIR system in terms of haplotypes, polymorphisms, expression patterns and their ligand interactions. These developments are delivering deeper insight into the relevance of KIR in immune system function, evolution and disease.

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Functional Polymorphism of the KIR3DL1/S1 Receptor on Human NK Cells

Cited by 148 publications

References 28 publications

Receptor systems controlling natural killer cell function are genetically stratified in Europe

Receptor systems controlling natural killer cell function are genetically stratified in Europe

KIR2DS1-Positive NK Cells Mediate Alloresponse against the C2 HLA-KIR Ligand Group In Vitro

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

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