scholarly journals Molecular Signatures of Natural Killer Cells in CMV-Associated Anterior Uveitis, A New Type of CMV-Induced Disease in Immunocompetent Individuals

2021 ◽  
Vol 22 (7) ◽  
pp. 3623
Author(s):  
Nobuyo Yawata ◽  
Mariko Shirane ◽  
Kaing Woon ◽  
Xinru Lim ◽  
Hidenori Tanaka ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Anterior Uveitis ◽  
Genetic Background ◽  
Nk Cell ◽  
Hla Class I ◽  
Class I ◽  
Molecular Signatures ◽  
Receptor Ligand ◽  
Ligand Interactions

Cytomegalovirus (CMV) causes clinical issues primarily in immune-suppressed conditions. CMV-associated anterior uveitis (CMV-AU) is a notable new disease entity manifesting recurrent ocular inflammation in immunocompetent individuals. As patient demographics indicated contributions from genetic background and immunosenescence as possible underlying pathological mechanisms, we analyzed the immunogenetics of the cohort in conjunction with cell phenotypes to identify molecular signatures of CMV-AU. Among the immune cell types, natural killer (NK) cells are main responders against CMV. Therefore, we first characterized variants of polymorphic genes that encode differences in CMV-related human NK cell responses (Killer cell Immunoglobulin-like Receptors (KIR) and HLA class I) in 122 CMV-AU patients. The cases were then stratified according to their genetic features and NK cells were analyzed for human CMV-related markers (CD57, KLRG1, NKG2C) by flow cytometry. KIR3DL1 and HLA class I combinations encoding strong receptor–ligand interactions were present at substantially higher frequencies in CMV-AU. In these cases, NK cell profiling revealed expansion of the subset co-expressing CD57 and KLRG1, and together with KIR3DL1 and the CMV-recognizing NKG2C receptor. The findings imply that a mechanism of CMV-AU pathogenesis likely involves CMV-responding NK cells co-expressing CD57/KLRG1/NKG2C that develop on a genetic background of KIR3DL1/HLA-B allotypes encoding strong receptor–ligand interactions.

Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 1935-1947 ◽  
Author(s):  
Sherif S. Farag ◽  
Todd A. Fehniger ◽  
Loredana Ruggeri ◽  
Andrea Velardi ◽  
Michael A. Caligiuri
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Natural Cytotoxicity ◽  
Receptor Ligand ◽  
Cell Receptors ◽  
Nk Cell Receptors ◽  
Ligand Interactions ◽  
Nk Receptor

AbstractNatural killer (NK) cells have held great promise for the immunotherapy of cancer for more than 3 decades. However, to date only modest clinical success has been achieved manipulating the NK cell compartment in patients with malignant disease. Progress in the field of NK cell receptors has revolutionized our concept of how NK cells selectively recognize and lyse tumor and virally infected cells while sparing normal cells. Major families of cell surface receptors that inhibit and activate NK cells to lyse target cells have been characterized, including killer cell immunoglobulinlike receptors (KIRs), C-type lectins, and natural cytotoxicity receptors (NCRs). Further, identification of NK receptor ligands and their expression on normal and transformed cells completes the information needed to begin development of rational clinical approaches to manipulating receptor/ligand interactions for clinical benefit. Indeed, clinical data suggest that mismatch of NK receptors and ligands during allogeneic bone marrow transplantation may be used to prevent leukemia relapse. Here, we review how NK cell receptors control natural cytotoxicity and novel approaches to manipulating NK receptor-ligand interactions for the potential benefit of patients with cancer.

Analysis of natural killer cells in TAP2-deficient patients: expression of functional triggering receptors and evidence for the existence of inhibitory receptor(s) that prevent lysis of normal autologous cells

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1723-1729 ◽  
Author(s):  
Massimo Vitale ◽  
Jacques Zimmer ◽  
Roberta Castriconi ◽  
Daniel Hanau ◽  
Lionel Donato ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Antigen Processing ◽  
Nk Cell ◽  
Hla Class I ◽  
Surface Expression ◽  
Class I ◽  
Inhibitory Receptor ◽  
Surface Receptors ◽  
Hla Class I Molecules

Natural killer (NK) cells are characterized by the ability to kill cells that lack HLA class I molecules while sparing autologous normal (HLA class I+) cells. However, patients with transporter-associated antigen processing (TAP) deficiency, though displaying strong reductions of HLA class I surface expression, in most instances do not experience NK-mediated autoimmune phenomena. A possible mechanism by which TAP−/− NK cells avoid autoreactivity against autologous HLA class I–deficient cells could be based on either quantitative or qualitative defects of surface receptors involved in NK cell triggering. In this study we show that NK cells derived from 2 patients with TAP2−/− express normal levels of all known triggering receptors. As revealed by the analysis of polyclonal and clonal NK cells, these receptors display normal functional capabilities and allow the killing of a panel of NK-susceptible targets, including autologous B-LCLs. On the other hand, TAP2−/− NK cells were unable to kill either allogeneic (HLA class I+) or autologous (HLA class I− ) phytohemagglutinin (PHA) blasts even in the presence of anti-HLA class I monoclonal antibody. These data suggest that TAP2−/− NK cells express still unknown inhibitory receptor(s) capable of down-regulating the NK cell cytotoxicity on binding to surface ligand(s) expressed by T cell blasts. Functional analyses, both at the polyclonal and at the clonal level, are consistent with the concept that the putative inhibitory receptor is expressed by virtually all TAP2−/− NK cells, whereas it is present only in rare NK cells from healthy persons. Another possibility would be that TAP2−/− NK cells are missing a still unidentified triggering receptor involved in NK cell-mediated killing of PHA blasts.

scholarly journals HLA upregulation during dengue virus infection suppresses the natural killer cell response

2019 ◽  
Author(s):  
Julia L. McKechnie ◽  
Davis Beltran ◽  
Arcelys Pitti ◽  
Lisseth Saenz ◽  
Ana B. Araúz ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Response ◽  
Nk Cell ◽  
Hla Class I ◽  
Denv Infection ◽  
Class I ◽  
Hla Class I Molecules

AbstractDengue virus (DENV) is the most prevalent mosquito-borne virus in the world and a major cause of morbidity in the tropics and subtropics. Upregulation of HLA class I molecules has long been considered a feature of DENV infection, yet this has not been evaluated in the setting of natural infection. Natural killer (NK) cells, an innate immune cell subset critical for mounting an early response to viral infection, are inhibited by self HLA class I, suggesting that upregulation of HLA class I during DENV infection could dampen the NK cell response. Here we addressed whether upregulation of HLA class I molecules occurs during in vivo DENV infection and, if so, whether this suppresses the NK cell response. We found that HLA class I expression was indeed upregulated during acute DENV infection across multiple cell lineages in vivo. To better understand the role of HLA class I upregulation, we infected primary human monocytes, a major target of DENV infection, in vitro. Upregulation of total HLA class I is dependent on active viral replication and is mediated in part by cytokines and other soluble factors induced by infection, while upregulation of HLA-E occurs in the presence of replication-incompetent virus. Importantly, blocking DENV-infected monocytes with a pan-HLA class I Fab nearly doubles the frequency of degranulating NK cells, while blocking HLA-E does not significantly improve the NK cell response. These findings demonstrate that upregulation of HLA class I during DENV infection suppresses the NK cell response, potentially contributing to disease pathogenesis.

Carfilzomib Enhances Natural Killer Cell-Mediated Lysis of Myeloma Linked with Decreasing Expression of HLA Class I

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1854-1854
Author(s):  
Jumei Shi ◽  
Guang Yang ◽  
Yuanyuan Kong ◽  
Minjie Gao ◽  
Yi Tao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nk Cells ◽  
Natural Killer ◽  
Hematological Malignancies ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Dependent Manner ◽  
Down Regulation

Abstract Multiple myeloma (MM) is a malignant disorder characterized by uncontrolled monoclonal plasma cell proliferation. It accounts for 10% of all hematological malignancies and causes 15-20% of deaths from hematological malignancies. Although new therapies were introduced and overall survival of MM was improved in the last 10 years, MM still remains an incurable disease due to drug resistance. Natural killer (NK) cell-based treatments are promising therapies for multiple myeloma (MM). Carfilzomib (CFZ), a second-generation proteasome inhibitor, is used to treat patients with MM who are refractory or intolerant to both bortezomib and lenalidomide (or thalidomide). In this study, we determined that CFZ treatment enhanced the sensitivity of MM cells to NK cell-mediated lysis. Here, we report that CFZ decreased the expression of human leukocyte antigen (HLA) class I on MM cell lines and primary MM cells, the mean reduction was 47.7 ± 9.4% and 42.8 ± 12.4%, respectively. The down-regulation caused by CFZ occurred in a dose- and time- dependent manner. We compared the cell surface levels of HLA class I on MM cells in the presence or absence of CFZ after acid treatment. CFZ also down-regulated the expression of newly formed HLA class I on MM cells. CD107a expression levels were used to measure NK-cell degranulation. When NK cells were incubated with MM cells with CFZ treatment, the percentage of NK cells expressing CD107a on the surface greatly increased (mean ± SD: 33.6 ± 2.1%, for treated cells vs 16.7 ± 2.3%, for control cells, P < 0.05). We also showed that CFZ augmented NK-cell cytotoxity by a perforin/granzyme-mediated mechanism, because such enhancement was abolished when CMA, but not anti-TRAIL or anti-Fas-L antibodies, was added. Treatment of MM with CFZ significantly sensitized patients' MM cells to NK cell-mediated lysis (mean ± SD: 43.1 ± 6.4%, for treated cells vs 16.1 ± 4.0%, for control cells at effector/target (E/T) ratio of 10:1, n = 9, P < 0.01). Furthermore, the exogenous HLA-C binding peptides, used in the CFZ treated group rescued the down-regulation of HLA-C and reduced NK cell-mediated lysis to a similar level as in the untreated group. Blocking NKG2D, NCRs and TRAIL did not have a significant impact on NK cell lysis of myeloma cells. These implied the enhancement of NK cell-mediated lysis was mainly linked with the decreased expression of HLA class I. Our findings show a novel activity of CFZ as an immunomodulating agent and suggest a possible approach to therapeutically augment NK cell function in MM patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Evolution and Immunogenetics of Natural Killer Cell Receptors in Health and Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-25-SCI-25
Author(s):  
Peter Parham
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Mhc Class I Molecules ◽  
Kir Gene ◽  
Kir Haplotypes

Abstract Natural killer (NK) cells are phenotypically diverse lymphocytes that contribute to innate immunity, adaptive immunity and placental reproduction. Unlike B and T cells, NK cells do not use rearranging genes to make diverse antigen receptors that are clonally expressed. Instead, NK cells express diverse combinations of a variety of receptors that are encoded by conventional non-rearranging genes. Several of these receptors are specific for conserved and variable determinants of major histocompatibility complex (MHC) class I molecules. In humans, the killer-cell immunoglobulin-like receptors (KIR) are a diverse and polymorphic family of NK-cell receptors that recognize determinants of human leukocyte antigen (HLA)-A, B and C, the polymorphic human MHC class I molecules. HLA-A, B and C are the most polymorphic of human genes, and they correlate with susceptibility to a wide range of diseases and clinical outcomes, including allogeneic hematopoietic cell transplantation (HCT). During NK-cell development, interactions between epitopes of HLA class I and KIR educate the NK cells to recognize the normal expression of these epitopes on healthy cells, and to respond to unhealthy cells in which that expression is perturbed. In the context of HCT, certain types of HLA class I mismatch enable donor-derived NK cells to make an alloreactive and beneficial graft-versus-leukemia response. Although it is likely that all placental mammals have NK cells, only a small minority of these species has a diverse KIR family like that in humans. These comprise the simian primates: New World monkeys, Old World monkeys and the great apes. Under pressure from diverse and rapidly evolving pathogens, both the MHC class I and KIR gene families have been driven to evolve rapidly. Consequently, much of their character is species-specific. This is especially true for the human KIR gene family, which is qualitatively different from that of our closest relatives, the chimpanzees. Whereas chimpanzee KIR haplotype diversity represents variations on a theme of genes encoding robust MHC class I receptors, humans have an even balance between group A KIR haplotypes encoding robust HLA class I receptors and group B KIR haplotypes encoding receptors that, to varying degree, have been subject to natural selection for reduced functional recognition of HLA class I. A balance of A and B is present in all human populations and thus appears essential for the long-term survival and competitiveness of human communities. Whereas the A KIR haplotypes correlate with successful defense against viral infection, maternal B KIR haplotypes correlate with reproductive success and donor B KIR haplotypes improve the outcome of allogeneic HCT as therapy for acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

Identification of Natural Killer Cell Receptor Phenotypes Associated with Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2997-2997
Author(s):  
Sonja J. Verheyden ◽  
Michel Bernier ◽  
Christian J. Demanet
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Cell Receptor ◽  
Innate Immune ◽  
Class I ◽  
Leukemic Cells ◽  
Hla Class I Molecules

Abstract Introduction: Natural Killer (NK) cells play a key role in defense against tumor cells that have the capacity to downregulate Human Leukocyte Antigen (HLA) class I expression. It has been reported that leukemic cells can have down-regulated expression of HLA class I molecules. Apparently, the NK cells of these patients are not able to destroy these leukemic cells and may allow malignant cells to escape from innate immune control. This failure may be due to the fact that NK cells are part of the malignant clone and therefore might have a decreased function. An alternative hypothesis could be that these patients may display a NK cell Receptor (NKR) genotype incapable of destroying leukemic cells with aberrant expression of HLA class I molecules. The polymorphic nature of the NKR genes generates diverse repertoires in the human population, which display specificity in the innate immune response. Materials and Methods: In the present study, 11 Killer cell Immunoglobulin-like Receptor (KIRs) and 2 CD94/NKG2 receptors were genotyped by PCR-SSP in 96 leukemic patients and 148 healthy Caucasians. Results and Conclusion: We report a significant increased frequency of the more inhibitory AB KIR phenotype in leukemic patients compared to the controls (31.1% in healthy controls vs. 51.0% in leukemic patients, Pc = 0.002), which is related to the high prevalence of the inhibitory KIR2DL2 in this population (Pc = 0.007). Moreover, two specific KIR phenotypes AB1 and AB9, including all inhibitory KIRs, were significantly associated with leukemic patients. Our study suggests that an important percentage of leukemic patients express a KIR phenotype in favor of escape from NK cell immunity.

Natural Killer Cell Activities Against iPSCs-Derived HLA-Knockout Platelets and Megakaryocytes Reveal Perfect Rejection Profiles for Allotransfusion

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3841-3841 ◽  
Author(s):  
Daisuke Suzuki ◽  
Naoshi Sugimoto ◽  
Norihide Yoshikawa ◽  
Hiroshi Endo ◽  
Sou Nakamura ◽  
...  
Keyword(s):  
Cytotoxic Activity ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Annexin V ◽  
Hla Class I ◽  
K562 Cells ◽  
Class I ◽  
Target Cells

Abstract Background Platelet transfusion refractoriness (PTR) due to immune factors occurs in 5-15% of thrombocytopenic patients who have received transfusions. The dominant cause of immune PTR is the production of allo-antibodies to human leukocyte antigen (HLA) class I, which is expressed on platelets. In current clinical settings, transfusion of HLA-compatible platelets is the only practical strategy, but their supply is weak due to limited donor source, gives excessive burden on specific donors, and requires increased efforts and costs. To overcome these issues, we plan to produce HLA-knockout platelets from iPSCs-derived megakaryocytes (MKs) as an alternative solution, applicable to all HLA types. However, whether they would be attacked by natural killer (NK) cells has not been well-studied. NK cells are known to show cytotoxic activity against cells downregulated for HLA class I ("missing self" theory). Therefore we assessed the interaction between HLA-knockout platelets derived from induced pluripotent stem cells (iPSCs) and NK cells in allogeneic settings. Methods and Results Immortalized megakaryocyte progenitor cell lines (imMKCLs) were previously established from iPSCs as a source of platelet production with a robust proliferation potential (Nakamura, 2014). Beta 2-microglobulin gene was knocked-out by CRISPR/Cas9 system to obtain HLA-knockout imMKCLs and platelets. NK cells were prepared from peripheral blood of eleven healthy donors. After co-cultures of NK cells and target cells for 6 hours with IL-2, we examined the NK cell cytolytic activity marker CD107, and target cell damage marker Annexin V using flow cytometry. Positive rates of both markers were not enhanced by co-culture with either HLA-expressed or HLA-knockout platelets for all donors. Furthermore, addition of platelets showed minimal effect on high cytotoxic activity of NK cells against K562 cells. In contrast, coculture of imMKCLs with NK cells resulted in higher detection of CD107 and Annexin V staining in some NK cell donors. These data suggested that platelets are immunologically inert for NK cells irrespective of class I HLA expression, while imMKCLs can be potentially attacked. Accordingly, platelets did not express NK cell activating ligands, which were expressed on imMKCLs and K562 cells. To confirm the above-mentioned results in vivo, mice were transfused with NK cells and platelets and MKs together. In our preliminary data, the circulation of platelets was not different between HLA-expressed or HLA-knockout type. In contrast, MKs were shown to be attacked in some cases. Conclusion HLA-knockout platelets evaded attacked from NK cells, while imMKCLs possessed immunogenicity to NK cells. This study provides extended experimental evidence that HLA-knockout platelets produced from a single imMKCL clone are immunologically applicable to all HLA types including majority of patients with PTR. On the other hand, contaminating imMKCLs in imMKCL-derived platelet products can be rejected by NK cells, contributing to their enhanced safety profiles. Taken together, stage of HLA-deficiency in imMKCLs as a starting material of platelet supply shall lead to industrial production of HLA universal platelets. Disclosures No relevant conflicts of interest to declare.

Decidual natural-killer-cell interaction with trophoblast: cytolysis or cytokine production?

2000 ◽  
Vol 28 (2) ◽  
pp. 196-198 ◽  
Author(s):  
Y. W. Loke ◽  
A. King
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Close Contact ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Target Cells ◽  
Hla Class I Antigens

At the implantation site, the uterine mucosa (decidua) is infiltrated by large numbers of natural killer (NK) cells. These NK cells are in close contact with the invading fetal trophoblast and we have proposed that they might be the effector cells that control the implantation of the allogeneic placenta. Recent characterization of NK cell receptors and their HLA class I ligands has suggested potential mechanisms by which NK cells might interact with trophoblast. However, what happens as a result of this interaction is not clear. The traditional method for investigating NK cell function in vitro is the protection from lysis of target cells by expression of HLA class I antigens. This might not be an accurate reflection of what happens in vivo. Another function of NK cells is the production of cytokines on contact with target cells. This could be an important outcome of the interaction between decidual NK cells and trophoblast. Decidual NK cells are known to produce a variety of cytokines; trophoblast cells express receptors for many of these cytokines, indicating that they can potentially respond. In this way, decidual NK cells have a significant influence on trophoblast behaviour during implantation.

scholarly journals The Education of NK Cells Determines Their Responsiveness to Autologous HIV-Infected CD4 T Cells

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Zahra Kiani ◽  
Franck P. Dupuy ◽  
Julie Bruneau ◽  
Bertrand Lebouché ◽  
Christelle Retière ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Hla Class I ◽  
Class I ◽  
Cell Responses ◽  
Infected Cells ◽  
Ifn Γ

ABSTRACT Several studies support a role for specific killer immunoglobulin-like receptor (KIR)–HLA combinations in protection from HIV infection and slower progression to AIDS. Natural killer (NK) cells acquire effector functions through education, a process that requires the interaction of inhibitory NK cell receptors with their major histocompatibility complex (MHC) class I (or HLA class I [HLA-I]) ligands. HLA-C allotypes are ligands for the inhibitory KIRs (iKIRs) KIR2DL1, KIR2DL2, and KIR2DL3, whereas the ligand for KIR3DL1 is HLA-Bw4. HIV infection reduces the expression of HLA-A, -B, and -C on the surfaces of infected CD4 (iCD4) T cells. Here we investigated whether education through iKIR-HLA interactions influenced NK cell responses to autologous iCD4 cells. Enriched NK cells were stimulated with autologous iCD4 cells or with uninfected CD4 cells as controls. The capacities of single-positive (sp) KIR2DL1, KIR2DL2, KIR2DL3, and KIR3DL1 NK cells to produce CCL4, gamma interferon (IFN-γ), and/or CD107a were assessed by flow cytometry. Overall, we observed that the potency of NK cell education was directly related to the frequency of each spiKIR+ NK cell’s ability to respond to the reduction of its cognate HLA ligand on autologous iCD4 cells, as measured by the frequency of production by spiKIR+ NK cells of CCL4, IFN-γ, and/or CD107a. Both NK cell education and HIV-mediated changes in HLA expression influenced NK cell responses to iCD4 cells. IMPORTANCE Epidemiological studies show that natural killer (NK) cells have anti-HIV activity: they are able to reduce the risk of HIV infection and/or slow HIV disease progression. How NK cells contribute to these outcomes is not fully characterized. We used primary NK cells and autologous HIV-infected cells to examine the role of education through four inhibitory killer immunoglobulin-like receptors (iKIRs) from persons with HLA types that are able to educate NK cells bearing one of these iKIRs. HIV-infected cells activated NK cells through missing-self mechanisms due to the downmodulation of cell surface HLA expression mediated by HIV Nef and Vpu. A higher frequency of educated than uneducated NK cells expressing each of these iKIRs responded to autologous HIV-infected cells by producing CCL4, IFN-γ, and CD107a. Since NK cells were from non-HIV-infected individuals, they model the consequences of healthy NK cell–HIV-infected cell interactions occurring in the HIV eclipse phase, when new infections are susceptible to extinction.

scholarly journals Roles for HLA and KIR polymorphisms in natural killer cell repertoire selection and modulation of effector function

2006 ◽  
Vol 203 (3) ◽  
pp. 633-645 ◽  
Author(s):  
Makoto Yawata ◽  
Nobuyo Yawata ◽  
Monia Draghi ◽  
Ann-Margaret Little ◽  
Fotini Partheniou ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Cell Surface Expression ◽  
Cell Repertoire ◽  
Hla Polymorphism ◽  
Cellular Expression

Interactions between killer cell immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands regulate the development and response of human natural killer (NK) cells. Natural selection drove an allele-level group A KIR haplotype and the HLA-C1 ligand to unusually high frequency in the Japanese, who provide a particularly informative population for investigating the mechanisms by which KIR and HLA polymorphism influence NK cell repertoire and function. HLA class I ligands increase the frequencies of NK cells expressing cognate KIR, an effect modified by gene dose, KIR polymorphism, and the presence of other cognate ligand–receptor pairs. The five common Japanese KIR3DLI allotypes have distinguishable inhibitory capacity, frequency of cellular expression, and level of cell surface expression as measured by antibody binding. Although KIR haplotypes encoding 3DL1*001 or 3DL1*005, the strongest inhibitors, have no activating KIR, the dominant haplotype encodes a moderate inhibitor, 3DL1*01502, plus functional forms of the activating receptors 2DL4 and 2DS4. In the population, certain combinations of KIR and HLA class I ligand are overrepresented or underrepresented in women, but not men, and thus influence female fitness and survival. These findings show how KIR–HLA interactions shape the genetic and phenotypic KIR repertoires for both individual humans and the population.

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