The Effect of Single and Combined Activating Killer Immunoglobulin-like Receptor Genotypes on Cytomegalovirus Infection and Immunity after Hematopoietic Cell Transplantation

Zaia, John A.; Sun, Ji; Gallez-Hawkins, Ghislaine; Thao, Lia; Oki, Aqsa Sjuhada; Lacey, Simon F.; Dagis, Andrew; Palmer, Joycelynne; Diamond, Don J.; Forman, Stephen J.; Senitzer, David

doi:10.1016/j.bbmt.2008.11.030

Cited by 86 publications

(83 citation statements)

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“…Similar studies have shown congruent results for donor activating KIR genotype in recipients of hematopoietic stem cell transplantation [7,8]. These data suggest that NK cells might recognize CMV-infected cells via activating KIR receptors.…”

Section: Introductionsupporting

confidence: 68%

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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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Section: Introductionsupporting

confidence: 68%

“…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%

Modulation of the natural killer cell KIR repertoire by cytomegalovirus infection

et al. 2012

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“…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). These studies analyzed KIR genotypes and/or KIR transcripts in HSCT donor/recipient pairs, but they did not analyze the effective size of NK cell subsets expressing activating KIRs or whether such KIRs were functional.…”

Section: Discussionmentioning

confidence: 78%

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

147

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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“…Furthermore, a case report shows a genetic mutation resulting in expression of the inhibitory receptor KIR2DL1 on the entire NK cell population leads to recurrent CMV infections (Gazit et al 2004). Additionally, during hematopoietic stem cell transplantation, a donor activating KIR profile is predictive for low risk of CMV reactivation (Zaia et al 2009). Recent evidence shows CMV infection induces clonal expansion of Vδ2 neg ɣδ T cells, with a highly differentiated effector memory phenotype, and enhanced effector function, suggesting a role for ɣδ T cells in CMV immunity (Roux et al 2013;Alejenef et al 2014;Khairallah et al 2017).…”

Section: Innate Immunitymentioning

confidence: 99%

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

Souquette¹,

Frere²,

Smithey³

et al. 2017

GeroScience

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Approximately 50% of individuals aged 6-49 years in the United States are infected with cytomegalovirus (CMV), with seroprevalence increasing with age, reaching 85-90% by 75-80 years according to Bate et al. (Clin Infect Dis 50 (11): 1439-1447 and Pawelec et al. (Curr Opin Immunol 24:507-511, 2012). Following primary infection, CMV establishes lifelong latency with periodic reactivation. Immunocompetent hosts experience largely asymptomatic infection, but CMV can cause serious illness in immunocompromised populations, such as transplant patients and the elderly. Control of CMV requires constant immune surveillance, and recent discoveries suggest this demand alters general features of the immune system in infected individuals. Here, we review recent advances in the understanding of the immune response to CMV and the role of CMV in immune aging and fitness, while highlighting the importance of potential confounding factors that influence CMV studies. Understanding how CMV contributes to shaping Bbaseline^immunity has important implications for a host's ability to mount effective responses to diverse infections and vaccination.

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The Effect of Single and Combined Activating Killer Immunoglobulin-like Receptor Genotypes on Cytomegalovirus Infection and Immunity after Hematopoietic Cell Transplantation

Cited by 86 publications

References 32 publications

Modulation of the natural killer cell KIR repertoire by cytomegalovirus infection

Modulation of the natural killer cell KIR repertoire by cytomegalovirus infection

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

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

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