A splice site mutation converts an inhibitory killer cell Ig-like receptor into an activating one

Blokhuis, Jeroen H.; Doxiadis, Gaby G. M.; Bontrop, Ronald E.

doi:10.1016/j.molimm.2008.08.270

Cited by 24 publications

(49 citation statements)

References 63 publications

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“…To determine the copy number of activating KIR genes in rhesus monkeys, we developed a quantitative real-time PCR assay (qPCR) using a primer/probe set that binds to a conserved region of KIR3DH genes that encodes the transmembrane domain of the KIR3DH proteins. This primer/probe set was designed to amplify 23 previously described KIR3DH alleles (GenBank accession numbers MmKIR3DH 1-4 (AF334648-AF334651), MmKIR3DH 7-21 (EU702453-EU702473), MmKIR3DH -like1-4 (AY505479-82)) [17], [18]. We confirmed that this primer/probe set does not bind inhibitory KIR genes by sequencing the qPCR amplicons (data not shown).…”

Section: Resultssupporting

confidence: 63%

“… KIR3DH cDNA clones of 8 unrelated rhesus monkeys with KIR3DH copy numbers ranging from 1–10 copies pdg were obtained using a PCR method described by Blokhuis et al [18]. Two previously reported KIR alleles (GU112262, GU112301) and ten novel KIR3DH alleles (JN613291-JN613300) were identified.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that there are five KIR receptor families in rhesus monkeys [17]. KIR3DH is the only activating KIR family in this nonhuman primate species, and this family of molecules is highly polymorphic [18]–[21]. An understanding of this KIR gene family of rhesus monkeys provides an important basis for exploring the contributions of KIR receptors and NK cells in early AIDS pathogenesis in the SIV/macaque model.…”

Section: Introductionmentioning

confidence: 99%

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Association of Activating KIR Copy Number Variation of NK Cells with Containment of SIV Replication in Rhesus Monkeys

et al. 2011

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While the contribution of CD8+ cytotoxic T lymphocytes to early containment of HIV-1 spread is well established, a role for NK cells in controlling HIV-1 replication during primary infection has been uncertain. The highly polymorphic family of KIR molecules expressed on NK cells can inhibit or activate these effector cells and might therefore modulate their activity against HIV-1-infected cells. In the present study, we investigated copy number variation in KIR3DH loci encoding the only activating KIR receptor family in rhesus monkeys and its effect on simian immunodeficiency virus (SIV) replication during primary infection in rhesus monkeys. We observed an association between copy numbers of KIR3DH genes and control of SIV replication in Mamu-A*01– rhesus monkeys that express restrictive TRIM5 alleles. These findings provide further evidence for an association between NK cells and the early containment of SIV replication, and underscore the potential importance of activating KIRs in stimulating NK cell responses to control SIV spread.

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Section: Resultssupporting

confidence: 63%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of Activating KIR Copy Number Variation of NK Cells with Containment of SIV Replication in Rhesus Monkeys

et al. 2011

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“…Based on comparative studies of primate species, a rapid evolution of the KIR gene system was proposed [25]. In the light of our intraspecies data, this proposal can be expanded to extremely rapid evolution.Since the repertoire is so diverse, it can be stated with confidence that in most biomedical studies the chance is very slim that rhesus macaques share a KIR genotype, in addition, this statement does not yet take into account the reported allelic variation [49]. However, by knowing the repertoire, one may consider the effects of individual KIR genes, since animals can be selected for the presence or absence of particular KIR.…”

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confidence: 99%

The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

et al. 2011

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NK cells are essential in shaping immune responses and play an important role during pregnancy and in controlling infections. Killer cell immunoglobulin-like receptors (KIRs) educate the NK cell and determine its state of activation. Our goal was to determine how the KIR repertoire of the rhesus macaque (Macaca mulatta) has been shaped during evolution. The presence or absence of 22 KIR gene groups was determined in 378 animals. Some unexpected observations were made in an outbred colony comprising animals of different origins. For instance, the KIR region appears to be highly plastic, and an unprecedented number of genotypes and haplotypes was observed. In contrast to humans, there is no distinction between group A and B haplotypes in the rhesus macaque, suggesting that different selective forces may be operative. Moreover, specific genes appear to be either present or absent in animals of different geographic origins. This extreme plasticity may have been propelled by co-evolution with the rhesus macaque MHC class I region, which shows signatures of expansion. The mosaic-like complexity of KIR genotypes as observed at the population level may represent an effective strategy for surviving epidemic infections. [3] but they are also involved with the vascularisation process during placentation, and thus contribute to reproductive success [4]. The education and activation state of the NK-cell is determined by the interactions of its receptors with their cognate ligands [5]. It is the shift in equilibrium of inhibitory and activating receptor signaling that ultimately leads to NK-cell activation in the form of cytokine production, cytotoxicity, or priming of the adaptive immune system [6].Killer cell immunoglobulin-like receptors (KIRs) may influence this balance through interactions with their ligands, the MHC molecules, which are called human leukocyte antigens 2719(HLA) in humans. Since both the HLA system and the KIR gene complex are characterized by variation in locus content, and segregate independent of each other, the potential array of interactions can vary considerably between individuals. Understanding the evolution and complexity of these receptor systems has broad medical relevance, since particular combinations of KIR and HLA alleles are associated with the outcome of viral infection, relapse of leukemia after transplantation, susceptibility to autoimmune disease, and successful pregnancy [7][8][9][10]. Because of its close evolutionary relationship to humans, and evidenced by similar immunological responses, the rhesus macaque (Macaca mulatta) is an important animal model to study the onset, progression, and outcome of infectious diseases, experimentally induced autoimmunity, and transplantation [11][12][13]. Moreover, certain human pathogens or their simiantrophic family members have adapted to primates as their natural host, and may show a host-specific pathology. Since in an experimental setting the onset of disease or the actual challenge with a pathogen can be controlled, it is possible to stu...

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“…We have recently demonstrated an association between specific NK cell subpopulations and the early containment of SIV replication in rhesus monkeys and a contribution of activating KIRs in stimulating NK cells to control the spread of SIV (8). In that study, we evaluated copy number variation (CNV) of KIR3DH, which represents an activating KIR receptor family in rhesus monkeys (4,9), and showed that KIR3DH copy numbers were negatively associated with SIV replication at the time of the early peak of viral replication in Mamu-A*01 Ϫ rhesus monkeys that express restrictive TRIM5 alleles. This observation implicated NK cells that express activating KIRs in controlling viral replication during early SIV infection.…”

mentioning

confidence: 99%

Activating KIR Copy Number Variation Is Associated with Granzyme B Release by NK Cells during Primary Simian Immunodeficiency Virus Infection in Rhesus Monkeys

Hellmann

Schmitz

Letvin

2012

J Virol

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Here we show that the number of activating killer cell immunoglobulin-like receptor (KIR) copies in rhesus monkeys is associated with the extent of release of cytotoxic granules by cytolytic NK cells during primary simian immunodeficiency virus SIVmac251 infection. These findings suggest that NK cells expressing high levels of activating KIRs efficiently kill SIVmac251-infected cells, and this efficient killing contributes to the NK cell-mediated control of replication of this virus during early infection. While it is well established that NK cells play a central role in the early control of a number of viral infections (11,18,22,23), their role in containing HIV-1 replication is only now being clarified. Studies have shown that activating killer cell immunoglobulin-like receptors (KIRs) that are expressed on NK cells are involved in controlling HIV-1 replication and slowing HIV-1 disease progression (1,2,15,17). While there is reason to suppose that NK cells affect HIV-1 replication early following infection, these cells are difficult to study during primary infection because it is difficult to obtain early blood samples from infected individuals. The simian immunodeficiency virus (SIV)-infected rhesus monkey provides an important nonhuman primate animal model for studying NK cell biology during a primary AIDS virus infection. We have recently demonstrated an association between specific NK cell subpopulations and the early containment of SIV replication in rhesus monkeys and a contribution of activating KIRs in stimulating NK cells to control the spread of SIV (8). In that study, we evaluated copy number variation (CNV) of KIR3DH, which represents an activating KIR receptor family in rhesus monkeys (4, 9), and showed that KIR3DH copy numbers were negatively associated with SIV replication at the time of the early peak of viral replication in Mamu-A*01 Ϫ rhesus monkeys that express restrictive TRIM5 alleles. This observation implicated NK cells that express activating KIRs in controlling viral replication during early SIV infection. However, the mechanism underlying this phenomenon remains unclear.The present study was initiated to determine how activating KIRs might affect SIV replication during primary infection. One important function of NK cells is to kill virus-infected target cells, and the present study assessed whether the cytolytic activity of NK cells is affected by KIR3DH CNV. In this study, the cytotoxicity of peripheral blood NK cells of Mamu-A*01 Ϫ rhesus monkeys was evaluated by measuring intracellular granzyme B and perforin levels and assessing CD107a surface expression on NK cells following in vitro stimulation with K562 cells, a cell line that does not express major histocompatibility complex (MHC) class I molecules (3,13,14). Peripheral blood mononuclear cells (PBMCs) were isolated from EDTA-anticoagulated whole blood by Ficoll-Paque (GE Healthcare, Piscataway, NJ) gradient separation and either stained immediately or cryopreserved in liquid nitrogen. After thawing, cryopreserved cells were ...

show abstract

A splice site mutation converts an inhibitory killer cell Ig-like receptor into an activating one

Cited by 24 publications

References 63 publications

Association of Activating KIR Copy Number Variation of NK Cells with Containment of SIV Replication in Rhesus Monkeys

Association of Activating KIR Copy Number Variation of NK Cells with Containment of SIV Replication in Rhesus Monkeys

The extreme plasticity of killer cell Ig‐like receptor (KIR) haplotypes differentiates rhesus macaques from humans

Activating KIR Copy Number Variation Is Associated with Granzyme B Release by NK Cells during Primary Simian Immunodeficiency Virus Infection in Rhesus Monkeys

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