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Eric O. Long - One of the best experts on this subject based on the ideXlab platform.
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Canonical and Cross-reactive Binding of NK Cell Inhibitory Receptors to HLA-C Allotypes Is Dictated by Peptides Bound to HLA-C.
Frontiers in Immunology, 2017Co-Authors: Malcolm J. W. Sim, Stacy A. Malaker, Ayesha Khan, Janet Stowell, Jeffrey Shabanowitz, Mary E. Peterson, Sumati Rajagopalan, Donald F. Hunt, Daniel M. Altmann, Eric O. LongAbstract:Abstract Background. Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys80). KIR2DL2 and KIR2DL3 bind HLA-C alleles of group C1 (Asn80). However, this model cannot explain HLA-C allelic effects in disease or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes. Results. The impact of HLA-C bound peptide on inhibitory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2, C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides or HIV Gag peptides by HLA-C can promote KIR cross-reactive binding. Conclusions. KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1 binding to C2, providing an explanation for KIR2DL3–C1 interactions appearing weaker than KIR2DL1–C2. In addition, cross-reactive binding of KIR is characterized by even higher peptide selectivity. We demonstrate a hierarchy of functional peptide selectivity of KIR–HLA-C interactions with relevance to NK cell biology and human disease associations. This selective peptide sequence-driven binding of KIR provides a potential mechanism for pathogen as well as self-peptide to modulate NK cell activation through altering levels of inhibition. Joint Corresponding Senior Authors.Email:eLong@nih.gov, r.boyton@imperial.ac.uk
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Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C
2016Co-Authors: Malcolm J. W. Sim, Stacy A. Malaker, Ayesha Khan, Janet Stowell, Jeffrey Shabanowitz, Mary E. Peterson, Sumati Rajagopalan, Donald F. Hunt, Daniel M. Altmann, Eric O. LongAbstract:Background. Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys80) and KIR2DL2 and KIR2DL3 bind HLA-C alleles of group C1 (Asn80). However, this model does not capture allelic diversity in HLA-C or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes. Results. The impact of HLA-C bound peptide on inhibitory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2, C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides, or predicted HIV Gag peptides, by HLA-C can promote KIR cross-reactive binding. Conclusions. KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1 binding to C2, which provides an explanation for why KIR2DL3-C1 interactions appear weaker than KIR2DL1-C2. In addition, cross-reactive binding of KIR is characterized by even higher peptide selectivity. We demonstrate a hierarchy of functional peptide selectivity of KIR-HLA-C interactions with relevance to NK cell biology and human disease associations. This selective peptide sequence-driven binding of KIR provides a potential mechanism for pathogen as well as self-peptide to modulate NK cell activation through altering levels of inhibition.
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KIR2DL3 and KIR2DL1 show similar impact on licensing of human NK cells
European journal of immunology, 2015Co-Authors: Malcolm J. W. Sim, Janet Stowell, Daniel M. Altmann, Eric O. Long, Ruhena Sergeant, Rosemary J. BoytonAbstract:Killer cell immunoglobulin-like receptor/HLA class I (KIR/HLA-I) combinations are associated with disease risk, implicating functional roles for NK cells (NKCs) or KIR(+) T cells. KIR/HLA-I interactions can act through inhibition of NKC activation by target cells and NKC licensing for greater intrinsic responsiveness. We compared licensing conferred by the weaker, HLA-C group 1/KIR2DL3, and the stronger, HLA-C group 2/KIR2DL1, inhibitory combinations. The "rheostat model" predicts weaker licensing by HLA-C1/KIR2DL3 interactions than HLA-C2/KIR2DL1. We analyzed degranulation in NKC subsets expressing single and multiple receptors for HLA-I. NKG2A had the strongest licensing impact, while KIR2DL3, KIR2DL1, and KIR3DL1 were weaker, and not significantly different to each other. Presence of one or two matched HLA-C allotypes did not alter licensing of KIR2DL3(+) and KIR2DL1(+) NKC. Coexpression of activating KIR2DS1 disarmed KIR2DL3(+) and KIR2DL1(+) NKC to a similar extent. KIR3DL1 and NKG2A combined for more enhanced licensing of double-positive NKC than the combination of KIR2DL3 and KIR2DL1. Thus, KIR2DL3 and KIR2DL1 have similar capacity to license NKC, suggesting that inhibitory signal strength and amount of available HLA-C ligands do not correlate with NKC licensing. Altogether, our results show that the basis for disease associations of HLA-C and KIR2DL likely encompasses factors other than licensing.
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NK Cell Proliferation Induced by IL-15 Transpresentation Is Negatively Regulated by Inhibitory Receptors.
Journal of immunology (Baltimore Md. : 1950), 2015Co-Authors: Olga M. Anton, Mary E. Peterson, Susina Vielkind, Yutaka Tagaya, Eric O. LongAbstract:IL-15 bound to the IL-15Rα-chain (IL-15Rα) is presented in trans to cells bearing the IL-2Rβ-chain and common γ-chain. As IL-15 transpresentation occurs in the context of cell-to-cell contacts, it has the potential for regulation by and of other receptor-ligand interactions. In this study, human NK cells were tested for the sensitivity of IL-15 transpresentation to inhibitory receptors. Human cells expressing HLA class I ligands for inhibitory receptors KIR2DL1, KIR2DL2/3, or CD94-NKG2A were transfected with IL-15Rα. Proliferation of primary NK cells in response to transpresented IL-15 was reduced by engagement of either KIR2DL1 or KIR2DL2/3 by cognate HLA-C ligands. Inhibitory KIR-HLA-C interactions did not reduce the proliferation induced by soluble IL-15. Therefore, transpresentation of IL-15 is subject to downregulation by MHC class I-specific inhibitory receptors. Similarly, proliferation of the NKG2A(+) cell line NKL induced by IL-15 transpresentation was inhibited by HLA-E. Coengagement of inhibitory receptors, either KIR2DL1 or CD94-NKG2A, did not inhibit phosphorylation of Stat5 but inhibited selectively phosphorylation of Akt and S6 ribosomal protein. IL-15Rα was not excluded from, but was evenly distributed across, inhibitory synapses. These findings demonstrate a novel mechanism to attenuate IL-15-dependent NK cell proliferation and suggest that inhibitory NK cell receptors contribute to NK cell homeostasis.
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KIR2DL4 (CD158d): An activation receptor for HLA-G
Frontiers in immunology, 2012Co-Authors: Sumati Rajagopalan, Eric O. LongAbstract:KIR2DL4 is an unusual killer cell immunoglobulin-like receptor (KIR) family member in terms of its structure, expression, cellular localization, and signaling properties. The most conserved KIR in evolution, it is referred to as a framework KIR gene and is expressed by all natural killer (NK) cells and a subset of T cells. Although it has a long cytoplasmic tail that is typical of inhibitory KIR, engagement of this receptor results in the activation of NK cells, not for cytotoxicity, but for cytokine and chemokine secretion. Unlike all other KIRs, which are expressed on the surface of NK cells, KIR2DL4 resides in endosomes. It signals from this intracellular site for a proinflammatory and proangiogenic response, using a novel endosomal signaling pathway that involves the serine/threonine kinases DNA-PKcs and Akt. The only known ligand of KIR2DL4 is HLA-G. Soluble HLA-G accumulates in KIR2DL4(+) endosomes. Unlike classical HLA molecules that serve as ligands for other KIR family members, in healthy individuals, HLA-G expression is restricted to the fetal trophoblast cells that invade the maternal decidua during early pregnancy. Since NK cells constitute the predominant lymphocyte subset at this site, the proinflammatory/proangiogenic outcome of the interaction between KIR2DL4 and soluble HLA-G supports a role for KIR2DL4 in the extensive remodeling of the maternal vasculature during the early weeks of pregnancy.
Zhihui Deng - One of the best experts on this subject based on the ideXlab platform.
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the novel KIR2DL4 038 allele identified by sequencing based typing in a chinese naxi individual
HLA, 2019Co-Authors: Jue Wang, Fuzhu Yao, Cai Siqi, Zhihui DengAbstract:The novel KIR2DL4*038 allele differs from the closest allele KIR2DL4*00102 by a single missense mutation.
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Identification of the novel KIR2DL4*036 allele in a Chinese Hani individual
HLA, 2019Co-Authors: Tonghua Yang, Fuzhu Yao, Siqi Cai, Zhihui DengAbstract:The novel KIR2DL4*036 allele differs from the closest allele KIR2DL4*00102 by a single missense mutation.
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identification of the novel KIR2DL4 036 allele in a chinese hani individual
HLA, 2019Co-Authors: Tonghua Yang, Fuzhu Yao, Siqi Cai, Zhihui DengAbstract:The novel KIR2DL4*036 allele differs from the closest allele KIR2DL4*00102 by a single missense mutation.
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The novel KIR2DL4*038 allele identified by sequencing-based typing in a Chinese Naxi individual
HLA, 2019Co-Authors: Jue Wang, Fuzhu Yao, Cai Siqi, Zhihui DengAbstract:The novel KIR2DL4*038 allele differs from the closest allele KIR2DL4*00102 by a single missense mutation.
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Description of the novel KIR2DL4*00603 allele identified in a Chinese Hani individual.
HLA, 2019Co-Authors: Tonghua Yang, Guobin Zhang, Zhihui DengAbstract:The novel KIR2DL4*00603 allele differs from the closest allele KIR2DL4*00602 by a silent mutation.
Weihua Yan - One of the best experts on this subject based on the ideXlab platform.
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Possible Roles of KIR2DL4 Expression on uNK Cells in Human Pregnancy
American journal of reproductive immunology (New York N.Y. : 1989), 2007Co-Authors: Weihua Yan, A. Lin, Bao-guo Chen, Mei-ying Zhou, Meizhen Dai, Xuejiao Chen, Linghong Gan, Min Zhu, Wei-wu ShiAbstract:Problem To investigate possible roles of the natural killer (NK) cell receptor killer immunoglobulin-like receptor (KIR)2DL4 expressed on uterine NK (uNK) cells during pregnancy, we investigated KIR2DL4 expression on uNK cells isolated from patients with early recurrent spontaneous abortion (RSA) and normal early pregnancy women, and functions of KIR2DL4 was analyzed in vitro. Methods of the study Semi-quantitative RT-PCR analysis was introduced to detect KIR2DL4 messenger RNA (mRNA) expression on uNK cells. Cytotoxicity and cytokine production as the result of interaction of KIR2DL4 and its ligand human leukocyte antigen (HLA)-G were analyzed in vitro with lactic dehydrogenase releasing method and enzyme-linked immunosorbent assay, respectively. Results No significant difference in KIR2DL4 mRNA expression was observed, while the KIR2DL4 protein level in isolated uNK cells is much higher in normal controls than that in RSA patients. Data showed that HLA-G transfection could not reverse the lysis of uNK against HLA-G transfected K562 cells but induced cytokine production. Furthermore, we demonstrated that, via KIR2DL4, membrane-bound HLA-G could induce high cytotoxicity and cytokine production in a high cytotoxic, IL-2 dependent human NK cell line NK-92 cells. Conclusion Our data suggest that KIR2DL4 might play a crucial implication for human pregnancy.
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Function of the residues Met~(76) and Gln~(79) in HLA--G alpha1 domain in KIR2DL4 recognition
2006Co-Authors: Weihua Yan, Aifen Lin, Lian FanAbstract:To investigate the biological function of the unique residues Met~(76) and Gln~(79) in HLA-G alpha1 domain in HLA-G specific receptor KIR2DL4 recognition. Eukaryotic vector CD41neg1 was applied to generate the soluble fusion protein KIR2DL4-IgG Fc. The codons encoding Met~(76) and Gln~(79) were mutated to Ala~(76,79) in HLA-G alpha1 domain with the methods of nest-PCR and point to point mutagenesis. Then, the wild and mutant HLA-G gene products were transfected into the HLA I molecules negative cell line K562 with retrovirus vector. The KIR2DL4 and HLA-G binding activity was measured with fluorescent density of KIR2DL4-IgG Fc binding to the wild and mutant HLA-G protein expressed in K562 cells. The function of the residues Met~(76) and Gln~(79) in KIR2DL4 recognition was evaluated by comparing the mean fluorescent density (MFI) of KIR2DL4-IgG Fc binding to the wild and mutant HLA-G molecules respectively. Western blot data showed that the fusion protein of KIR2DL4-IgG Fc protein was successfully expressed and the FACS results revealed that the wild and mutant HLA-G was expressed in K562 cells. Mutating Met~(76), Gln~(79) to Ala~(76,79) could remarkably effect the binding activity of the MIR2DL4 to HLA-G molecules. Met~(76), Gln~(79) in the HLA-G alpha1 domain could be the key residues involved in the KIR2DL4 recognition.
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Residues Met 76 and Gln 79 in HLA-G α1 domain involved in KIR2DL4 recognition
Cell research, 2005Co-Authors: Weihua Yan, Lian FanAbstract:Human leukocyte antigen-G (HLA-G) has long been speculated as a beneficial factor for a successful pregnancy for its restricted expression on fetal-maternal extravillous cytotrophoblasts and its capability of modulating uterine natural killer cell (uNK) function such as cytotoxicity and cytokine production through NK cell receptors. HLA class I α1 domain is an important killer cell Ig-like receptor (KIR) recognition site and the Met76 and Gln79 are unique to HLA-G in this region. NK cell receptor KIR2DL4 is a specific receptor for HLA-G, yet the recognition site on HLA-G remains unknown. In this study, retroviral transduction was applied to express the wild type HLA-G (HLA-wtG), mutant HLA-G (HLA-mG) on the chronic myelogenous leukemia cell line K562 cells and KIR2DL4 molecule on NK-92 cells, respectively. KIR2DL4-IgG Fc fusion protein was generated to determine the binding specificity between KIR2DL4 and HLA-G. Our results showed that residue Met76 , Gln79 mutated to Ala76, 79 in the α1 domain of HLA-G protein could affect the binding affinity between KIR2DL4 and HLA-G, meanwhile, the KIR2DL4 transfected NK-92 cells (NK-92-2DL4) showed a considerably different cytolysis ability against the HLA-wtG and HLA-mG transfected K562 targets. Taken together, our data indicated that residue Met76 and Gln79 in HLA-G α1 domain plays a critical role in the recognition of KIR2DL4, which could be an explanation for the isoforms of HLA-G, all containing the α1 domain, with the potential to regulate NK functions.
Piotr Kuśnierczyk - One of the best experts on this subject based on the ideXlab platform.
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Possible Role of HLA-G, LILRB1 and KIR2DL4 Gene Polymorphisms in Spontaneous Miscarriage.
Archivum immunologiae et therapiae experimentalis, 2016Co-Authors: Izabela Nowak, Andrzej Malinowski, Ewa Barcz, Jacek R. Wilczyński, Marta Wagner, Edyta Majorczyk, Hanna Motak-pochrzest, Małgorzata Banasik, Piotr KuśnierczykAbstract:The KIR2DL4 receptor and its ligand HLA-G are considered important for fetal-maternal immune tolerance and successful pregnancy. The absence of a particular variant of KIR2DL4 might be a bad prognostic factor for pregnancy outcome. However, it could be compensated by the presence of the respective LILRB1 allele. Therefore, we investigated the KIR2DL4, LILRB1 and HLA-G polymorphisms in 277 couples with spontaneous abortion and 219 control couples by HRM, PCR-SSP and RFLP methods. We found a protective effect of women's heterozygosity in -716 HLA-G (p = 0.0206) and LILRB1 (p = 0.0131) against spontaneous abortion. Surprisingly, we observed more 9A/10A genotypes of KIR2DL4 gene carriers in the group of male partners from the miscarriage group in comparison to the men from the control group (p = 0.0288). Furthermore, there was no association of women's KIR2DL4 polymorphism with susceptibility to spontaneous abortion. Multivariate analysis indicated that women's -716 HLA-G and LILRB1 and men's KIR2DL4 9A/10A are important in terms of the protection or susceptibility to miscarriage, respectively (p = 0.00968). In conclusion, a woman's heterozygosity in HLA-G and LILRB1 might be an advantage for a success of reproduction, but the partner's heterozygosity in 9A/10A KIR2DL4 alleles might not.
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Two new cases of KIR3DP1, KIR2DL4-negative genotypes, one of which is also lacking KIR3DL2.
Archivum immunologiae et therapiae experimentalis, 2014Co-Authors: Wanda Niepiekło-miniewska, Natalia Żuk, Joanna Dubis, Maciej Kurpisz, David Senitzer, Anna Havrylyuk, Ryszard Grendziak, Wojciech Witkiewicz, Valentyna Chopyak, Piotr KuśnierczykAbstract:The killer immunoglobulin-like receptor (KIR) genes KIR2DL4, KIR3DL2, and KIR3DP1 are present in virtually all humans. KIR2DL4 encodes a receptor present on uterine and decidual natural killer (NK) cells and some peripheral blood NK cells. Its only known ligand is the human leukocyte antigen-G molecule expressed on extravillous trophoblasts, and on tissues in some diseases. KIR3DL2 binds HLA-A*03 and HLA-A*11 as well as HLA-B*27 dimers, and microbial CpG DNA. KIR3DP1 is a pseudogene. During our immunogenetic studies we found two individuals, one from Lower Silesia district in Poland, and another from Western Ukraine, who were reproducibly negative for KIR2DL4 and KIR3DP1 genes, using three different PCR systems. Both individuals displayed very similar genotypes, possessing only KIR3DL3, KIR2DL3, KIR2DP1, KIR2DS1, and probably a rare variant of KIR2DL1. The Pole had also KIR3DL2, which the Ukrainian was apparently lacking. The Lower Silesia has been populated after the Second World War by a remarkable percentage with displaced people from Western Ukraine, which might contribute to genetic similarity of the two individuals described here.
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Lack of KIR2DL4 gene in a fertile Caucasian woman.
Tissue antigens, 2011Co-Authors: Izabela Nowak, David Senitzer, Edyta Majorczyk, Rafał Płoski, Ji-yao Sun, Piotr KuśnierczykAbstract:Killer cell immunoglobulin-like receptor (KIR2DL4) gene is present in virtually all humans. It encodes a receptor present on uterine and decidual natural killer (NK) cells and some peripheral blood NK cells. Its only known ligand is human leukocyte antigen-G molecule expressed on extravillous trophoblasts invading the decidua. Therefore, KIR2DL4 has been regarded as a molecule important for successful pregnancy. However, a multiparous woman from Africa, lacking KIR2DL4 gene, was described suggesting that this gene is not absolutely required for successful human reproduction. Here, we describe a Polish woman who delivered a child and who is not only lacking KIR2DL4 gene, but also possessing a KIR genotype virtually identical to that of the African woman mentioned above. Their genotypes are compared with few other KIR2DL4-negative genotypes and haplotypes described so far.
Sumati Rajagopalan - One of the best experts on this subject based on the ideXlab platform.
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Canonical and Cross-reactive Binding of NK Cell Inhibitory Receptors to HLA-C Allotypes Is Dictated by Peptides Bound to HLA-C.
Frontiers in Immunology, 2017Co-Authors: Malcolm J. W. Sim, Stacy A. Malaker, Ayesha Khan, Janet Stowell, Jeffrey Shabanowitz, Mary E. Peterson, Sumati Rajagopalan, Donald F. Hunt, Daniel M. Altmann, Eric O. LongAbstract:Abstract Background. Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys80). KIR2DL2 and KIR2DL3 bind HLA-C alleles of group C1 (Asn80). However, this model cannot explain HLA-C allelic effects in disease or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes. Results. The impact of HLA-C bound peptide on inhibitory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2, C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides or HIV Gag peptides by HLA-C can promote KIR cross-reactive binding. Conclusions. KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1 binding to C2, providing an explanation for KIR2DL3–C1 interactions appearing weaker than KIR2DL1–C2. In addition, cross-reactive binding of KIR is characterized by even higher peptide selectivity. We demonstrate a hierarchy of functional peptide selectivity of KIR–HLA-C interactions with relevance to NK cell biology and human disease associations. This selective peptide sequence-driven binding of KIR provides a potential mechanism for pathogen as well as self-peptide to modulate NK cell activation through altering levels of inhibition. Joint Corresponding Senior Authors.Email:eLong@nih.gov, r.boyton@imperial.ac.uk
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Canonical and cross-reactive binding of NK cell inhibitory receptors to HLA-C allotypes is dictated by peptides bound to HLA-C
2016Co-Authors: Malcolm J. W. Sim, Stacy A. Malaker, Ayesha Khan, Janet Stowell, Jeffrey Shabanowitz, Mary E. Peterson, Sumati Rajagopalan, Donald F. Hunt, Daniel M. Altmann, Eric O. LongAbstract:Background. Human natural killer (NK) cell activity is regulated by a family of killer-cell Ig-like receptors (KIR) that bind human leucocyte antigen (HLA) class I. Combinations of KIR and HLA genotypes are associated with disease, including susceptibility to viral infection and disorders of pregnancy. KIR2DL1 binds HLA-C alleles of group C2 (Lys80) and KIR2DL2 and KIR2DL3 bind HLA-C alleles of group C1 (Asn80). However, this model does not capture allelic diversity in HLA-C or the impact of HLA-bound peptides. The goal of this study was to determine the extent to which the endogenous HLA-C peptide repertoire can influence the specific binding of inhibitory KIR to HLA-C allotypes. Results. The impact of HLA-C bound peptide on inhibitory KIR binding was investigated taking advantage of the fact that HLA-C*05:01 (HLA-C group 2, C2) and HLA-C*08:02 (HLA-C group 1, C1) have identical sequences apart from the key KIR specificity determining epitope at residues 77 and 80. Endogenous peptides were eluted from HLA-C*05:01 and used to test the peptide dependence of KIR2DL1 and KIR2DL2/3 binding to HLA-C*05:01 and HLA-C*08:02 and subsequent impact on NK cell function. Specific binding of KIR2DL1 to the C2 allotype occurred with the majority of peptides tested. In contrast, KIR2DL2/3 binding to the C1 allotype occurred with only a subset of peptides. Cross-reactive binding of KIR2DL2/3 with the C2 allotype was restricted to even fewer peptides. Unexpectedly, two peptides promoted binding of the C2 allotype-specific KIR2DL1 to the C1 allotype. We showed that presentation of endogenous peptides, or predicted HIV Gag peptides, by HLA-C can promote KIR cross-reactive binding. Conclusions. KIR2DL2/3 binding to C1 is more peptide selective than that of KIR2DL1 binding to C2, which provides an explanation for why KIR2DL3-C1 interactions appear weaker than KIR2DL1-C2. In addition, cross-reactive binding of KIR is characterized by even higher peptide selectivity. We demonstrate a hierarchy of functional peptide selectivity of KIR-HLA-C interactions with relevance to NK cell biology and human disease associations. This selective peptide sequence-driven binding of KIR provides a potential mechanism for pathogen as well as self-peptide to modulate NK cell activation through altering levels of inhibition.
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KIR2DL4 (CD158d): An activation receptor for HLA-G
Frontiers in immunology, 2012Co-Authors: Sumati Rajagopalan, Eric O. LongAbstract:KIR2DL4 is an unusual killer cell immunoglobulin-like receptor (KIR) family member in terms of its structure, expression, cellular localization, and signaling properties. The most conserved KIR in evolution, it is referred to as a framework KIR gene and is expressed by all natural killer (NK) cells and a subset of T cells. Although it has a long cytoplasmic tail that is typical of inhibitory KIR, engagement of this receptor results in the activation of NK cells, not for cytotoxicity, but for cytokine and chemokine secretion. Unlike all other KIRs, which are expressed on the surface of NK cells, KIR2DL4 resides in endosomes. It signals from this intracellular site for a proinflammatory and proangiogenic response, using a novel endosomal signaling pathway that involves the serine/threonine kinases DNA-PKcs and Akt. The only known ligand of KIR2DL4 is HLA-G. Soluble HLA-G accumulates in KIR2DL4(+) endosomes. Unlike classical HLA molecules that serve as ligands for other KIR family members, in healthy individuals, HLA-G expression is restricted to the fetal trophoblast cells that invade the maternal decidua during early pregnancy. Since NK cells constitute the predominant lymphocyte subset at this site, the proinflammatory/proangiogenic outcome of the interaction between KIR2DL4 and soluble HLA-G supports a role for KIR2DL4 in the extensive remodeling of the maternal vasculature during the early weeks of pregnancy.
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Activation of NK cells by an endocytosed receptor for soluble HLA-G.
PLoS biology, 2005Co-Authors: Sumati Rajagopalan, Irma Joosten, Yenan T. Bryceson, Shanmuga P Kuppusamy, Daniel E. Geraghty, Arnold Van Der Meer, Eric O. LongAbstract:Signaling from endosomes is emerging as a mechanism by which selected receptors provide sustained signals distinct from those generated at the plasma membrane. The activity of natural killer (NK) cells, which are important effectors of innate immunity and regulators of adaptive immunity, is controlled primarily by receptors that are at the cell surface. Here we show that cytokine secretion by resting human NK cells is induced by soluble, but not solid-phase, antibodies to the killer cell immunoglobulin-like receptor (KIR) 2DL4, a receptor for human leukocyte antigen (HLA)-G. KIR2DL4 was constitutively internalized into Rab5-positive compartments via a dynamin-dependent process. Soluble HLA-G was endocytosed into KIR2DL4-containing compartments in NK cells and in 293T cells transfected with KIR2DL4. Chemokine secretion induced by KIR2DL4 transfection into 293T cells occurred only with recombinant forms of KIR2DL4 that trafficked to endosomes. The profile of genes up-regulated by KIR2DL4 engagement on resting NK cells revealed a proinflammatory/proangiogenic response. Soluble HLA-G induced secretion of a similar set of cytokines and chemokines. This unique stimulation of resting NK cells by soluble HLA-G, which is endocytosed by KIR2DL4, implies that NK cells may provide useful functions at sites of HLA-G expression, such as promotion of vascularization in maternal decidua during early pregnancy.
