Phenotypic and Functional Analyses of KIR3DL1+ and KIR3DS1+ NK Cell Subsets Demonstrate Differential Regulation by Bw4 Molecules and Induced KIR3DS1 Expression on Stimulated NK Cells

Morvan, Maelig; Willem, Catherine; Gagne, Katia; Kerdudou, Nolwenn; David, Grégoire; Sébille, Véronique; Folléa, Gilles; Bignon, Jean-Denis; Retière, Christelle

doi:10.4049/jimmunol.0900212

Cited by 29 publications

(30 citation statements)

References 57 publications

(67 reference statements)

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“…PBMCs were isolated as previously described (15,18). All blood donors were recruited at the Blood Transfusion Center (Etablissement Français du Sang, Nantes, France), and informed consent was given by all donors.…”

Section: Cells (Pbmcs and Cell Lines)mentioning

confidence: 99%

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Large Spectrum of HLA-C Recognition by Killer Ig–like Receptor (KIR)2DL2 and KIR2DL3 and Restricted C1 Specificity of KIR2DS2: Dominant Impact of KIR2DL2/KIR2DS2 on KIR2D NK Cell Repertoire Formation

David

Djaoud

Willem

et al. 2013

The Journal of Immunology

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The interactions of killer Ig–like receptor 2D (KIR2D) with HLA-C ligands contribute to functional NK cell education and regulate NK cell functions. Although simple alloreactive rules have been established for inhibitory KIR2DL, those governing activating KIR2DS function are still undefined, and those governing the formation of the KIR2D repertoire are still debated. In this study, we investigated the specificity of KIR2DL1/2/3 and KIR2DS1/2, dissected each KIR2D function, and assessed the impact of revisited specificities on the KIR2D NK cell repertoire formation from a large cohort of 159 KIR and HLA genotyped individuals. We report that KIR2DL2+ and KIR2DL3+ NK cells reacted similarly against HLA-C+ target cells, irrespective of C1 or C2 allele expression. In contrast, KIR2DL1+ NK cells specifically reacted against C2 alleles, suggesting a larger spectrum of HLA-C recognition by KIR2DL2 and KIR2DL3 than KIR2DL1. KIR2DS2+ KIR2DL2− NK cell clones were C1-reactive irrespective of their HLA-C environment. However, when KIR2DS2 and KIR2DL2 were coexpressed, NK cell inhibition via KIR2DL2 overrode NK cell activation via KIR2DS2. In contrast, KIR2DL1 and KIR2DS2 had an additive enhancing effect on NK cell responses against C1C1 target cells. KIR2DL2/3/S2 NK cells predominated within the KIR repertoire in KIR2DL2/S2+ individuals. In contrast, the KIR2DL1/S1 NK cell compartment is dominant in C2C2 KIR2DL2/S2− individuals. Moreover, our results suggest that together with KIR2DL2, activating KIR2DS1 and KIR2DS2 expression limits KIR2DL1 acquisition on NK cells. Altogether, our results suggest that the NK cell repertoire is remolded by the activating and inhibitory KIR2D and their cognate ligands.

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Section: Cells (Pbmcs and Cell Lines)mentioning

confidence: 99%

“…HLA class I allele assignment and KIR gene content typing were performed as previously described (15,18). KIR haplotypes were determined as previously described (6).…”

Section: Hla and Kir Genotypingmentioning

confidence: 99%

Large Spectrum of HLA-C Recognition by Killer Ig–like Receptor (KIR)2DL2 and KIR2DL3 and Restricted C1 Specificity of KIR2DS2: Dominant Impact of KIR2DL2/KIR2DS2 on KIR2D NK Cell Repertoire Formation

David

Djaoud

Willem

et al. 2013

The Journal of Immunology

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“…After co-culture with CMV-infected MRC-5, NK cells remained negative for KIR2DL1 and KIR2DL3, demonstrating that the increase in expression of the respective KIR was most likely due to expansion of KIR + NK cells rather than induction of KIR expression in KIR − NK cells (data not shown). As KIR3DS1 expression is detectable only barely above background staining on primary NK cells [20], flow cytometric sorting of KIR3DS1 + from KIR3DS1 − cells was not possible, and formal proof that the increase in KIR3DS1 detected after exposure to CMV is still lacking.…”

Section: Increase In Inhibitory Kir Expression Is Due To Expansion Ofmentioning

confidence: 99%

Modulation of the natural killer cell KIR repertoire by cytomegalovirus infection

et al. 2012

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Patients carrying activating killer cell immunoglobulin-like receptor (KIR) genes are significantly protected from CMV-associated complications after solid organ or hematopoietic stem cell transplantation. Whether previous infection with CMV affects NK-cell function in healthy donors is unknown. We studied the KIR repertoire and alterations of KIR expression after in vitro exposure to CMV in 54 healthy donors. The expression of neither activating nor inhibitory KIRs was different at baseline between 23 seropositive and 31 seronegative donors. However, after co-culture of NK cells with CMV-infected fibroblast cells, expression of the inhibitory receptors KIR2DL1 and KIR2DL3 and the activating receptor KIR3DS1 significantly increased in CMV-seropositive donors. In CMVseronegative donors, changes were subtle and restricted to the subset of NK cells expressing NK-cell group antigen 2C (NKG2C). Expansion of inhibitory KIRs occurred exclusively in donors carrying the cognate HLA class I ligands, whereas the presence of the putative ligand HLA-Bw4 was not necessary for the expansion of KIR3DS1-expressing NK cells. Our data show that previous infection with CMV does not alter the resting NK-cell receptor repertoire, but appears to modify how NK cells respond to re-exposure to CMV in vitro.Keywords: CMV r KIR r Natural killer cells Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction NK cells are an important component of the immune system in the control of viral infection [1]. Unlike B and T cells, NK cells do not display rearranged receptors but instead are regulated by the integration of signaling from germline encoded activating and inhibitory receptors. One important and incompletely characterized family of receptors are the killer cell immunoglobulin-like receptors (KIRs) [2]. KIRs are almost exclusively expressed on NK cells and encoded by 15 different gene loci, nine inhibitory iKIRs, and six activating aKIRs. The KIR genes cluster in chromosome 19, Correspondence: Prof. Martin Stern e-mail: sternm@uhbs.ch forming haplotypes composed of 7-11 individual KIR genes. The most common haplotype in Caucasians contains mostly iKIRs accompanied by a single or no aKIR gene and is called "A" haplotype [3]. Haplotypes containing more than one aKIR gene are collectively termed "B" haplotypes. Most iKIRs recognize HLA class I ligands and function as important receptors in the maintenance of NK-cell self-tolerance. In contrast, neither the ligands nor the function of most aKIRs have been established [4].We have recently shown in patients undergoing solid organ transplantation a protective effect of B haplotype genes regarding posttransplant CMV infection and reactivation [5,6]. * These authors contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2013. 43: 480-487 Innate immunity 481Similar studies have shown congruent results for donor activating KIR genotype in recipients of hematopoietic stem cell transplantation [7,8]. These data sugg...

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“…PBMCs were isolated as previously described (24,25). Thereafter, NK cells were amplified after in vitro stimulation with irradiated C1 + and C2…”

Section: Nk Cell Isolation and Amplificationmentioning

confidence: 99%

Amplified NKG2C+ NK Cells in Cytomegalovirus (CMV) Infection Preferentially Express Killer Cell Ig-like Receptor 2DL: Functional Impact in Controlling CMV-Infected Dendritic Cells

Djaoud

David

Bressollette

et al. 2013

The Journal of Immunology

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CMV infection represents a major complication in hematopoietic stem cell transplantation, which compromises graft outcome. Downregulation of HLA class I expression is one mechanism by which CMV evades T cell–mediated immune detection, rendering infected cells vulnerable to killer cell Ig-like receptor (KIR)+ NK cells. In this study, we observed that the amplified NKG2C+ NK cell population observed specifically in CMV seropositive individuals mainly expressed KIR2DL receptors. We have shown that HLA class I expression was downregulated on CMV-infected immature dendritic cells (iDCs), which escape to HLA-A2-pp65–specific T lymphocytes but strongly trigger the degranulation of KIR2D+ NK cells. CMV infection conferred a vulnerability of C2C2+ iDCs to educated KIR2DL1+ and KIR2DL3+ NK cell subsets. Alloreactivity of KIR2DL1+ NK cell subsets against C1C1+ iDCs was maintained independently of CMV infection. Unexpectedly, CMV-infected C1C1+ iDCs did not activate KIR2DL3+ NK cell reactivity, suggesting a potential CMV evasion to KIR2DL3 NK cell recognition. Altogether, the coexpression of KIR and NKG2C on expanded NK cell subsets could be related to a functional contribution of KIR in CMV infection and should be investigated in hematopoietic stem cell transplantation, in which the beneficial impact of CMV infection has been reported on the graft-versus-leukemia effect.

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Phenotypic and Functional Analyses of KIR3DL1+ and KIR3DS1+ NK Cell Subsets Demonstrate Differential Regulation by Bw4 Molecules and Induced KIR3DS1 Expression on Stimulated NK Cells

Cited by 29 publications

References 57 publications

Large Spectrum of HLA-C Recognition by Killer Ig–like Receptor (KIR)2DL2 and KIR2DL3 and Restricted C1 Specificity of KIR2DS2: Dominant Impact of KIR2DL2/KIR2DS2 on KIR2D NK Cell Repertoire Formation

Large Spectrum of HLA-C Recognition by Killer Ig–like Receptor (KIR)2DL2 and KIR2DL3 and Restricted C1 Specificity of KIR2DS2: Dominant Impact of KIR2DL2/KIR2DS2 on KIR2D NK Cell Repertoire Formation

Modulation of the natural killer cell KIR repertoire by cytomegalovirus infection

Amplified NKG2C+ NK Cells in Cytomegalovirus (CMV) Infection Preferentially Express Killer Cell Ig-like Receptor 2DL: Functional Impact in Controlling CMV-Infected Dendritic Cells

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