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At least 19 recordsLinked to original sources

PubMed2006

Influence of interleukin IL-2 and IL-12 + IL-18 on surface expression of immunoglobulin-like receptors KIR2DL1, KIR2DL2, and KIR3DL2 in natural killer cells.

Natural killer (NK) cells express killer cell inhibitory receptors (KIRs) that recognize polymorphic class I MHC molecules. In the present study, we analyze the modulatory effect of IL-2 alone or a combination of IL-12 with IL-18 on surface expression of killer cell immunoglobulin-like receptors KIR2DL1, KIR2DL2, and KIR3DL2 in NK cells. Thus, it was found that IL-2 causes a significant increase in the proportion of cells with given studied receptors. Stimulation by a mixture of IL-12 and IL-18 caused significant increase in the fraction of cells with the KIR2DL1 and KIR2DL2, however no significant change in the percentage of cells with KIR3DL2 receptor on their surface was observed. The results of the study show the presence of KIRs on both resting and activated NK cells, this may suggest that KIRs have also an important role in the regulatory processes after activation of this subpopulation of cells.

Cells, Cultured↗

PubMed2005

Expression of inhibitory-motif killer immunoglobulin-like receptor, KIR2DL1, is increased in natural killer cells from women with pelvic endometriosis.

PROBLEM: We investigated inhibitory and activation motif expression of killer immunoglobulin-like receptor (KIR) by natural killer (NK) cells, which may be pathogenetically involved in endometriosis. METHOD OF STUDY: We compared cells from 24 Japanese women laparoscopically diagnosed with endometriosis, to cells from 25 women with other laparoscopic diagnoses. KIR expression by NK cells was assessed in peripheral blood (PB) and peritoneal fluid (PF) by flow cytometry. Intracellular immunoreceptor tyrosine-based (IT) inhibitory and activation motifs (ITIM and ITAM) of KIR in PB was assessed by Western blotting. RESULTS: ITIM-KIR expression by PB NK cells was significantly and similarly greater than ITAM-KIR expression in women with and without endometriosis. Percentages of CD56(+) NK cells in PB and PF did not differ significantly between women with and without endometriosis; however, the percentage of CD158a(+) cells among CD56(+) NK cells in PB and PF was significantly higher in women with than without endometriosis. CONCLUSIONS: ITIM-KIR expressing NK cells might confer tolerance to peritoneal endometriotic implants.

Blotting, Western↗

PubMed2002

Increased killer inhibitory receptor KIR2DL1 expression among natural killer cells in women with pelvic endometriosis.

OBJECTIVE: To investigate the host immunologic response to endometriosis in terms of killer inhibitory receptor (KIR) expression by natural killer (NK) cells. DESIGN: Case-control study of immunologic markers. SETTING: University hospital. PATIENT(S): We compared cells from Japanese women with laparoscopically diagnosed endometriosis to cells from 40 women with other laparoscopic diagnoses. INTERVENTION(S): Peripheral venous blood sampling and laparoscopic peritoneal fluid collection. MAIN OUTCOME MEASURE(S): Flow cytometry was used to assess expression of KIR by NK cells in the cell samples. RESULT(S): The percentage of cells that expressed KIR2DL1 among NK (KIR2DL1(+)NK) cells in peritoneal fluid and peripheral blood was significantly higher in women with endometriosis than in controls. The proportion of KIR2DL1(+)NK cells in peripheral blood NK cells before and 1 month after laparoscopic surgery did not differ significantly. CONCLUSION(S): The proportion of KIR2DL1(+)NK cells was increased in peritoneal fluid and peripheral blood in women with endometriosis; this difference is probably related to NK cell suppression in endometriosis. This increase in KIR2DL1 expression by NK cells may represent a risk factor in the pathogenesis of endometriosis.

Adult↗

PubMed2001

Crystal structure of the human natural killer cell inhibitory receptor KIR2DL1-HLA-Cw4 complex.

Inhibitory natural killer (NK) cell receptors down-regulate the cytotoxicity of NK cells upon recognition of specific class I major histocompatibility complex (MHC) molecules on target cells. We report here the crystal structure of the inhibitory human killer cell immunoglobulin-like receptor 2DL1 (KIR2DL1) bound to its class I MHC ligand, HLA-Cw4. The KIR2DL1-HLA-Cw4 interface exhibits charge and shape complementarity. Specificity is mediated by a pocket in KIR2DL1 that hosts the Lys80 residue of HLA-Cw4. Many residues conserved in HLA-C and in KIR2DL receptors make different interactions in KIR2DL1-HLA-Cw4 and in a previously reported KIR2DL2-HLA-Cw3 complex. A dimeric aggregate of KIR-HLA-C complexes was observed in one KIR2DL1-HLA-Cw4 crystal. Most of the amino acids that differ between human and chimpanzee KIRs with HLA-C specificities form solvent-accessible clusters outside the KIR-HLA interface, which suggests undiscovered interactions by KIRs.

Dimerization↗

PubMed2000

Cobalt-mediated dimerization of the human natural killer cell inhibitory receptor.

Upon engagement of specific class I major histocompatibility complex (MHC) molecules on target cells, inhibitory receptors on natural killer (NK) cells deliver a negative signal that prevents the target cell lysis by NK cells. In humans, killer cell immunoglobulin-related receptors (KIR) with two immunoglobulin-like domains (KIR2D) modulate the lysis of target cells bearing specific HLA-C alleles (Moretta, A., Vitale, M., Bottino, C., Orengo, A. M., Morelli, L., Augugliaro, R., Barbaresi, M., Ciccone, E., and Moretta, L. (1993) J. Exp. Med. 178, 597-604). The transduction of inhibitory signals by KIR2D molecules is impaired by the zinc chelator, 1,10-phenanthroline, and mutation of a putative zinc-binding site (Rajagopalan, S., and Long, E. O. (1998) J. Immunol. 161, 1299-1305), but the mechanism by which zinc may affect the function of KIR remains unknown. In this study, the inhibitory NK receptor KIR2DL1 was discovered to dimerize in the presence of Co(2+) as observed on native gel electrophoresis and by gel filtration column chromatography. Furthermore, Co(2+)-mediated KIR2DL1 dimer binds to HLA-Cw4 with higher affinity than the wild type KIR2DL1 monomer. Replacement of the amino-terminal His residue by Ala abolishes the ability of KIR2DL1 to bind Co(2+), indicating that Co(2+)-mediated KIR2DL1 dimerization involves pairing of the D1 domain. Although not observed on native gels, the inhibitory receptor KIR2DL1 can be chemically cross-linked into dimers in the presence of Zn(2+) and its related divalent metal ions, suggesting that Co(2+)-mediated dimerization of KIR2DL1 may mimic a weaker interaction between KIR2DL1 and zinc in vivo.

Binding Sites↗

PubMed2004

Gene for the activating natural killer cell receptor, KIR2DS1, is associated with susceptibility to psoriasis vulgaris.

Psoriasis vulgaris, particularly its juvenile form, is strongly associated with the HLA-Cw*06 allele encoding the HLA-Cw6 molecule. This molecule is recognized by the inhibitory receptor KIR2DL1 and the activatory receptor KIR2DS1, which are expressed on natural killer cells and subpopulations of T lymphocytes. Humans differ by the presence or absence of particular KIR genes. We hypothesized that either activatory KIR2DS1 or inhibitory KIR2DL1 gene frequencies might be different in psoriatic patients from a control population. Therefore, we compared the frequencies of KIR2D inhibitory (L) and activatory (S) genes in 116 psoriasis vulgaris patients and in 123 healthy controls. Fourteen novel gene combinations were found. KIR2DS1 was present in 85% of the patients, but only in 51% of the controls (corrected p [pc] < 0.0009). Similarly, HLA-Cw*06 was much more frequent in patients (77%) than in controls (17%; pc < 0.00002). Statistical analysis suggests that, although the contribution of these two factors to psoriasis is partially independent, they interact nevertheless. This result strongly speaks for a role of KIR2DS1 on recognition of HLA-Cw6 in susceptibility to psoriasis.

Adult↗

PubMed2002

KIR2DL4 (CD158d), an NK cell-activating receptor with inhibitory potential.

KIR2DL4 (CD158d) is an unusual member of the killer cell Ig-like receptor family expressed in all NK cells and some T cells. KIR2DL4 activates the cytotoxicity of NK cells, despite the presence of an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic tail. The role of this ITIM on the activating function of KIR2DL4, and whether it can provide inhibitory signals, is not known. Mutated forms of KIR2DL4 were engineered that lacked either the tyrosine in the ITIM or an arginine-tyrosine motif in the transmembrane region that is required for the activation signal. The activity of the mutated KIR2DL4 molecules was tested in a redirected lysis assay. The ITIM was not necessary for activation of lysis by KIR2DL4. The activation signal of KIR2DL4 was sensitive to inhibition by another ITIM-containing receptor. The activation-deficient mutant of KIR2DL4 inhibited the signal delivered by the activating receptor CD16. In pull-down experiments with GST fusion proteins, the tyrosine-phosphorylated cytoplasmic tail of KIR2DL4 bound the Src homology 2-containing phosphatases 1 and 2, as did the tail of the inhibitory receptor KIR2DL1. Therefore, KIR2DL4 has inhibitory potential in addition to its activating function.

Amino Acid Motifs↗

PubMed1999

Crystal structure of the human p58 killer cell inhibitory receptor (KIR2DL3) specific for HLA-Cw3-related MHC class I.

BACKGROUND: T cells and natural killer (NK) cells perform complementary roles in the cellular immune system. T cells identify infected cells directly through recognition of antigenic peptides that are displayed at the target cell surface by the classical major histocompatibility complex (MHC) class I molecules. NK cells monitor the target cell surface for malfunction of this display system, lysing potentially infected cells that might otherwise evade recognition by the T cells. Human killer cell inhibitory receptors (KIRs) control this process by either inhibiting or activating the cytotoxic activity of NK cells via specific binding to MHC class I molecules on the target cell. RESULTS: We report the crystal structure of the extracellular region of the human p58 KIR (KIR2DL3), which is specific for the human MHC class I molecule HLA-Cw3 and related alleles. The structure shows the predicted topology of two tandem immunoglobulin-like domains, but comparison with the previously reported structure of the related receptor KIR2DL1 reveals an unexpected change of 23 degrees in the relative orientation of these domains. CONCLUSIONS: The altered orientation of the immunoglobulin-like domains maintains an unusually acute interdomain elbow angle, which therefore appears to be a distinctive feature of the KIRs. The putative MHC class I binding site is located on the outer surface of the elbow, spanning both domains. The unexpected observation that this binding site can be modulated by differences in the relative domain orientations has implications for the general mechanism of KIR-MHC class I complex formation.

Amino Acid Sequence↗

PubMed2000

A disulfide-linked natural killer cell receptor dimer has higher affinity for HLA-C than wild-type monomer.

Inhibitory receptors on the surface of natural killer (NK) cells recognize specific MHC class I molecules on target cells and prevent the target cell lysis by NK cells. The killer cell immunoglobulin-related receptors (KIR), KIR2D, found in human, specifically interact with polymorphic HLA-C molecules. The crystal structure of the inhibitory receptor, KIR2DL1, revealed a relationship to the hematopoietic receptor family, suggesting that the signaling mechanism of KIR2D molecules may resemble that of the hematopoietic receptors, and involve KIR2D dimerization. We have engineered a disulfide-linked dimer of KIR2DL1 by introducing a free cysteine at the C-terminal stem region of the receptor. The disulfide-linked KIR2DL1 dimer binds to HLA-Cw4 at a molar ratio of one dimer to one HLA-Cw4 molecule. Furthermore, the covalently-linked KIR2DL1 dimer binds more tightly to HLA-Cw4 than the wild-type monomer, suggesting the occurrence of a second binding event that increases the overall affinity of KIR dimer for HLA-C.

Dimerization↗

PubMed2001

CD56bright cells differ in their KIR repertoire and cytotoxic features from CD56dim NK cells.

In this study we present new differential characteristics of NK cells expressing CD56 surface antigen in low (CD56dim) or high (CD56bright) density. In contrast to CD56bright NK cells CD56dim cells express killer cell immunoglobulin (Ig)-like receptors (KIR) such as CD158a, CD158b, and NKB1. However, c-type lectin-like receptors (KLR) CD94/NKG2 and CD161 are present on both subsets. The ability to form conjugates with susceptible targets is approximately twice as strongly pronounced in CD56dim vs. CD56bright NK cells. Last but not least, granules of CD56dim cells contain about tenfold more perforin and granzyme A enabling potentially more effective cytolysis compared to CD56bright NK cells. On the other hand, CD56bright NK cells are superior in producing the proinflammatory cytokines IFN-gamma (28.5% vs. 20.8%, p<0.05) and TNF-alpha (28% vs. 15.8%, p<0.001). The different NK cell populations retained their specific phenotype in vitro during culture in the presence of IL-2 contradicting that they simply display different stages of maturity. Taken together our data support the view that CD56bright cells are specialized NK cells that regulate immunological response mechanisms rather by cytokine supply than by their cytotoxic potential. The poor cytolytic capacity of CD56bright NK cells can be explained by weak ability in forming conjugates with target cells and low contents of perforin and granzyme A in their granules.

Antigens, CD↗

PubMedDate not supplied

Immunophenotypic characterization of normal blood CD56+lo versus CD56+hi NK-cell subsets and its impact on the understanding of their tissue distribution and functional properties.

In the present study we have compared the immunophenotypic characteristics of the CD56+lo and CD56+hi NK-cell subsets in a group of normal healthy adults. Our results show that CD56+hi NK-cells display greater light-scatter properties than CD56+lo NK-cells at the same time they have higher levels of CD25 and CD122 IL-2 chains, together with a higher reactivity for HLA-DR and CD45RO and lower levels of CD45RA, supporting that, as opposed to the majority of the CD56+lo population, CD56+hi NK-cells might correspond to a subset of activated circulating NK-lymphocytes. Higher expression of the CD2 and CD7 costimulatory molecules found for the CD56+hi NK-cells would support their greater ability to respond to various stimuli. In addition, CD56+hi NK-cells expressed higher levels of several adhesion molecules such as CD2, CD11c, CD44, CD56, and CD62L compared to CD56+lo NK-cells, supporting a particular ability of these cells to migrate from blood to tissues and/or a potential advantage to form conjugates with target cells. Interestingly, CD56+lo and CD56+hi NK-cells showed a different pattern of expression of killer receptors that might determine different activation requirements for each of these NK-cell subsets. For instance, absence or low levels of CD16 expression might explain the lower antibody-dependent cytotoxicity activity of CD56+hi NK-cells. On the other hand, the virtual absence of expression of the CD158a and NKB1 immunoglobulin-like and the greater reactivity for the CD94 lectin-like killer receptors on CD56+hi in comparison to CD56+lo NK-cells might determine different MHC-class I specificities for both NK-cell subsets, a possibility that deserves further studies to be confirmed.

Adult↗

PubMed2000

The genomic organization and evolution of the natural killer immunoglobulin-like receptor (KIR) gene cluster.

Natural killer (NK) immunoglobulin-like receptors (KIRs) are a family of polymorphic receptors which interact with specific motifs on HLA class I molecules and modulate NK cytolytic activity. In this study, we analyzed a recently sequenced subgenomic region on chromosome 19q13.4 containing eight members of the KIR receptor repertoire. Six members are clustered within a 100-kb continuous sequence. These genes include a previously unpublished member of the KIR gene family 2DS6, as well as 2DL1, 2DL4, 3DL1, 2DS4, 3DL2, from centromere to telomere. Two additional KIR genes, KIRCI and 2DL3, which may be located centromeric of this cluster were also analyzed. We show that the KIR genes have undergone repeated gene duplications. Diversification between the genes has occurred postduplication primarily as a result of retroelement indels and gene truncation. Using pre- and postduplication Alu sequences identified within these genes as evolutionary molecular clocks, the evolution and duplication of this gene cluster is estimated to have occurred 30-45 million years ago, during primate evolution. A proposed model of the duplication history of the KIR gene family leading to their present organization is presented.

Alleles↗

PubMed2002

Selective reduction of natural killer cells and T cells expressing inhibitory receptors for MHC class I in the livers of patients with hepatic malignancy.

Natural killer (NK) and CD56(+) T cells are thought to play a central role in antitumour immunity. Their cytolytic activities are controlled by a variety of receptors including CD94 and killer immunoglobulin-like receptors (KIR), which bind to major histocompatibility complex (MHC) class I molecules on target cells and mediate cell activation or inhibition. We have examined the numbers, phenotypes and antitumour cytotoxic functions of hepatic NK and CD56(+) T cells isolated from 22 patients with hepatic malignancy and 19 healthy donors. Flow cytometry revealed that NK cell numbers were increased among hepatic mononuclear cells in malignancy compared to histologically normal livers (mean: 38% vs 27%; P=0.03), but CD56(+) T cell numbers were not (28% vs 27%). NK cells and CD56(+) T cells from tumour-bearing livers exhibited lymphokine-activated killing of K562 targets and T cell receptor-mediated lysis of P815 cells. The expression of CD94 and the KIR isotypes CD158a, CD158b and KIR3DL1 by CD56(+) T cells and NK cells was significantly and consistently reduced in tumour-bearing livers compared to healthy livers ( P<0.05 in all cases). Simultaneous ligation of CD158a, CD158b and KIR3DL1 caused an overall partial inhibition of CD56(+) T cell cytotoxic activity, suggesting that the observed reductions in KIR(+) cell numbers in malignancy are likely to lead to enhanced cytotoxicity. Our results suggest that, while hepatic CD56(+) T cells are not expanded in malignancy, downregulation of KIR and CD94 expression may be a mechanism by which the hepatic immune system can be activated to facilitate tumour rejection.

Adenocarcinoma↗

PubMed2003

Abnormal killer inhibitory receptor expression on natural killer cells in patients with Behçet's disease.

Viral infection has been assigned some role in the pathogenesis of Behçet's disease (BD). Defects in natural killer (NK) cell repertoire may be involved in impaired antiviral immunity, leading to the development of BD. We studied killer inhibitory receptor (KIR) expression in 40 patients with BD. CD94 and CD158b expression of NK cells was normal in a great majority of BD patients. NKB1 expression was reduced in eight and increased in six. Twelve of these 14 patients (86%) had severe eye disease. Some had reduced NKB1 and enhanced CD158a expression simultaneously, or enhanced NKB1 and reduced CD158a simultaneously, suggesting a skewed NK cell repertoire in BD. Collectively, KIR expression was abnormal in the BD patients with severe eye disease. This may result from genetic predisposition, or certain viruses may affect the KIR repertoire formation in BD patients. Abnormal KIR expression of NK cells may be associated with the development of BD.

Adult↗

PubMed2006

KIR gene in ethnic and Mestizo populations from Mexico.

Killer cell immunoglobulin-like receptors are characterized by their great diversity of genes and alleles. Population studies have identified the presence of a broad variety of genotypes. In Mexico, there are diverse ethnic groups representing 9% of the total population and the rest is composed of Mestizos with a more varied biology. For the purpose of this study, genotyping was performed in Mestizos, in Mexico City inhabitants, and in three ethnic groups. The frequencies of genes KIR2DL2, 2DL5, 2DS1-3, 2DS5, and 3DS1 showed a greater variability in the groups studied. A total of 12 different genotypes were identified, the higher number for the Mestizos and the lower number for the Tarahumaras. Genotype 1 was found at a greater frequency in all the groups, except for the Tarahumaras, in which genotype 4 was more frequent. The frequency of genotypes 4 and 8 in Mexicans was higher than that for other populations analyzed. By subtyping of KIR3DL1, 3DL2, 2DL1, and 2DL3, two B haplotypes were identified in families; both were absent in Caucasian families. Our results indicated a greater diversity of genes in the Mestizos group than in the ethnic groups.

American Indian or Alaska Native↗

PubMed2006

Analysis of KIR2D receptors on peripheral blood lymphocytes from liver graft recipients.

KIR2D receptors are killer cell immunoglobulin-like receptors (KIRs) specific for HLA-C epitopes, that are expressed on NK cells as well as on minor peripheral blood T-cell subsets, and are able to control NK and T cells activity. The present work explores NK, and particularly CD8(+) T cells expressing KIR2D2L1/S1 (CD158a) or KIR2D2L2/3/S2 (CD158b) receptors in liver graft alloresponse. Flow cytometry was used to analyse peripheral blood mononuclear cells stained with anti-CD158a and anti-CD158b antibodies from 110 liver recipients and 46 healthy controls, previous to and along the first month after transplantation. Pre-transplantation data shows that both CD158a and CD158b molecules can be detected on NK and T cells from all patients and controls, but both KIR2D(+)NK cells are significantly under-represented in patients respect to controls (P<0.001), and CD3(+)CD8(+)CD158a(+) cells decreased particularly in patients suffering from acute rejection (4.03+/-1.33 cells/microL) compared with controls (7.8+/-2.4 cells/microL). Following transplantation, KIR2D(+)CD8(+) T-cell repertoires increased through the first month, mainly in recipients with a good graft acceptance. In summary, monitoring of KIR2D(+)CD8(+) T cells, particularly KIR2DL1/S1(+)CD8(+) T cells at pre-transplant, and both KIR2DL1/S1(+) and KIR2DL2/3/S2(+) T-cell subsets at early post-transplant period, could offer useful information for clinical follow-up of liver grafts.

Acute Disease↗

PubMed2001

Distribution of the natural killer-related receptor for HLA-C during highly active antiretroviral therapy for human immunodeficiency virus infection.

Receptors interacting with Major Histocompatibility Complex class I molecules have been initially found on the surface of human natural killer (NK) cells, where they deliver inhibitory signals to the lysis, being thus defined killer inhibitory receptors (KIR). Subsequently, they were detected also on the surface of T-CD8(+) lymphocytes and are particularly expanded during human immunodeficiency virus (HIV) infection, where they downregulate HIV-specific cytolysis. The expression of KIR recognizing human leukocyte antigen-C alleles was assessed in HIV-infected patients, undergoing highly active antiretroviral therapy (HAART). To this end, the combined expression of CD16/CD56, of CD3 and CD8 as well as of KIR (CD158a and CD158b) surface molecules was analyzed on peripheral blood mononuclear cells by monoclonal antibodies, and flow cytometry. An increase of CD3(+)CD8(+)CD158b(+) cells was found after 6 months of HAART. This finding may have implications for the regulation of T-cell mediated cytolysis during HAART.

Adult↗

PubMed2002

NK cells become Ki-67+ in MLC and expand depending on the lack of ligand for KIR on stimulator cells in IL-2 supplemented MLC.

Mixed lymphocyte culture (MLC) response was measured with the use of Ki-67 monoclonal antibody and responding cells were verified by CD3 and CD56 surface markers staining. Stimulator cells were discriminated from responder cells on the basis of forward and side scatter. Allogeneic, but not autologous MLC had Ki-67+ responder cells in lymphocyte gate at the end of the culture. In allogeneic MLC T cells and natural killer (NK) cells were in a similar proportion Ki-67+ (mean +/- SD: 59.25% +/- 9.72% versus 61.75% +/- 13.2%). Ki-67+ NK cells had higher CD56 mean fluorescence intensity than those lacking Ki-67 (745+/-357 versus 196+/-56 p < 0.0001). NK cells contribution to responding lymphocytes was positively correlated with the percentage of Ki67+ cells in NK population by the end of the culture (r = 0.74, p = 0.002). NK cells response in MLC increased upon supplementation of the culture medium with human recombintant interleukin-2 (IL-2). Responder cells from single individual were tested with 8 Bw4+ and 8 Bw4- as well as with 9 CNK1+ and 9 CNK1- stimulators. In IL-2 supplemented MLC killer inhibitory receptor expressing cells expanded when ligands for this receptor were absent in stimulating population. Consequently, stimulator cells lacking Bw4 promoted NKB1+ cells expansion (7.2% +/- 3% versus 3.6% +/- 1%, p = 0.0031), whereas HLA-C NK1 negative stimulators promoted CD158a+ cells expansion (9.6% +/- 4.8% versus 6% +/- 2.6%, p = 0.0385).

CD3 Complex↗