The Number of Activating KIR Genes Inversely Correlates with the Rate of CMV Infection/Reactivation in Kidney Transplant Recipients

Stangel, Martin; Elsässer, Hanno; Hönger, Gideon; Steiger, J.; Schaub, Stefan; Hess, Christoph

doi:10.1111/j.1600-6143.2008.02242.x

Cited by 94 publications

(93 citation statements)

References 17 publications

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“…For example, in HIV-seropositive individuals coexpressing KIR3DS1 and HLA-Bw4, progression toward AIDS is delayed (37). A reduced risk of HCMV reactivation has been reported in solid organ transplantation recipients carrying more than one activating KIR (38,39), as well as in patients given HSCT from donors expressing more than one activating KIR (40). The best protective effect was detected in patients whose donors had a KIR genotype with more than five activating KIRs or containing simultaneously KIR2DS2 and KIR2DS4 (41).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Infection Promotes Rapid Maturation of NK Cells Expressing Activating Killer Ig–like Receptor in Patients Transplanted with NKG2C−/− Umbilical Cord Blood

Chiesa

Falco

Bertaina

et al. 2014

The Journal of Immunology

145

113

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NK cells are the first lymphoid population recovering after allogeneic hematopoietic stem cell transplantation and play a crucial role in early immunity after the graft. Recently, it has been shown that human CMV (HCMV) infection/reactivation can deeply influence NK cell reconstitution after umbilical cord blood transplantation by accelerating the differentiation of mature NKG2A−killer Ig-like receptor (KIR)+ NK cells characterized by the expression of the NKG2C-activating receptor. In view of the hypothesis that NKG2C could be directly involved in NK cell maturation driven by HCMV infection, we analyzed the maturation and function of NK cells developing in three patients with hematological malignancies given umbilical cord blood transplantation from donors carrying a homozygous deletion of the NKG2C gene. We show that HCMV infection can drive rapid NK maturation, characterized by the expansion of CD56dimNKG2A−KIR+ cells, even in the absence of NKG2C expression. Interestingly, this expanded mature NK cell subset expressed surface-activating KIR that could trigger NK cell cytotoxicity, degranulation, and IFN-γ release. Given the absence of NKG2C, it is conceivable that activating KIRs may play a role in the HCMV-driven NK cell maturation and that NK cells expressing activating KIRs might contribute, at least in part, to the control of infections after transplantation.

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Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Infection Promotes Rapid Maturation of NK Cells Expressing Activating Killer Ig–like Receptor in Patients Transplanted with NKG2C−/− Umbilical Cord Blood

Chiesa

Falco

Bertaina

et al. 2014

The Journal of Immunology

145

113

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“…This analysis of the impact of previous infection with CMV on the KIR repertoire of NK cells was prompted by the observation that transplant recipients are relatively protected from CMV replication if they carried B-haplotype associated activating KIR genes [5][6][7][8].…”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

“…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.…”

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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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“…In HLA haploidentical HSCT, NK cell alloreactivity is due to the presence in the donor of NK cells expressing KIR that recognize HLA class I allotypes present in the donor but absent in the recipient (16). KIR genotypic studies have revealed the beneficial effect of activating KIR genes against CMV infection or reactivation in different graft contexts (16)(17)(18). During acute CMV infection, NKG2C…”

mentioning

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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The Number of Activating KIR Genes Inversely Correlates with the Rate of CMV Infection/Reactivation in Kidney Transplant Recipients

Cited by 94 publications

References 17 publications

Human Cytomegalovirus Infection Promotes Rapid Maturation of NK Cells Expressing Activating Killer Ig–like Receptor in Patients Transplanted with NKG2C−/− Umbilical Cord Blood

Human Cytomegalovirus Infection Promotes Rapid Maturation of NK Cells Expressing Activating Killer Ig–like Receptor in Patients Transplanted with NKG2C−/− Umbilical Cord Blood

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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