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.

scholarly journals Relevance of Polymorphic KIR and HLA Class I Genes in NK-Cell-Based Immunotherapies for Adult Leukemic Patients

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3767
Author(s):  
Léa Dubreuil ◽  
Patrice Chevallier ◽  
Christelle Retière ◽  
Katia Gagne
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Current Knowledge ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Cell Repertoire ◽  
Hematopoietic Stem ◽  
Structural Formation ◽  
The Impact

Since the mid-1990s, the biology and functions of natural killer (NK) cells have been deeply investigated in healthy individuals and in people with diseases. These effector cells play a particularly crucial role after allogeneic hematopoietic stem-cell transplantation (HSCT) through their graft-versus-leukemia (GvL) effect, which is mainly mediated through polymorphic killer-cell immunoglobulin-like receptors (KIRs) and their cognates, HLA class I ligands. In this review, we present how KIRs and HLA class I ligands modulate the structural formation and the functional education of NK cells. In particular, we decipher the current knowledge about the extent of KIR and HLA class I gene polymorphisms, as well as their expression, interaction, and functional impact on the KIR+ NK cell repertoire in a physiological context and in a leukemic context. In addition, we present the impact of NK cell alloreactivity on the outcomes of HSCT in adult patients with acute leukemia, as well as a description of genetic models of KIRs and NK cell reconstitution, with a focus on emergent T-cell-repleted haplo-identical HSCT using cyclosphosphamide post-grafting (haplo-PTCy). Then, we document how the immunogenetics of KIR/HLA and the immunobiology of NK cells could improve the relapse incidence after haplo-PTCy. Ultimately, we review the emerging NK-cell-based immunotherapies for leukemic patients in addition to HSCT.

scholarly journals Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell–mediated lysis of myeloma

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1309-1317 ◽  
Author(s):  
Jumei Shi ◽  
Guido J. Tricot ◽  
Tarun K. Garg ◽  
Priyangi A. Malaviarachchi ◽  
Susann M. Szmania ◽  
...  
Keyword(s):  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Expression ◽  
Class I ◽  
Cell Surface Expression ◽  
Significant Activity

AbstractHuman leukocyte antigen class I molecules expressed by tumor cells play a central role in the regulation of natural killer (NK) cell–mediated immune responses. The proteasome inhibitor bortezomib has demonstrated significant activity in multiple myeloma (MM). We hypothesized that treatment of MM with bortezomib results in the reduction of cell-surface expression of class I and thereby sensitizes MM to NK cell–mediated lysis. Here we report that bortezomib down-regulates class I in a time- and dose-dependent fashion on all MM cell lines and patient MM cells tested. Downregulation of class I can also be induced in vivo after a single dose of 1.0 mg/m2 bortezomib. Bortezomib significantly enhances the sensitivity of patient myeloma to allogeneic and autologous NK cell–mediated lysis. Further, the level of decrease in class I expression correlates with increased susceptibility to lysis by NK cells. Clinically relevant bortezomib concentrations do not affect NK-cell function. Our findings have clear therapeutic implications for MM and other NK cell–sensitive malignancies in the context of both allogeneic and autologous adoptively transferred NK cells.

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 Adaptive Admixture of HLA class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians

2021 ◽  
Author(s):  
Zhihui Deng ◽  
Jianxin Zhen ◽  
Genelle F Harrison ◽  
Guobin Zhang ◽  
Rui Chen ◽  
...  
Keyword(s):  
Natural Killer ◽  
High Frequency ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Telomeric Region ◽  
East Asians ◽  
Cell Functions ◽  
Specific Receptors

Abstract Human natural killer (NK) cells are essential for controlling infection, cancer and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B and -C genes, we show that the Chinese Southern Han are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the Chinese Southern Han KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B specific receptors. In all these characteristics, the Chinese Southern Han represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity and effector strength, likely augmenting resistance to endemic viral infections.

scholarly journals Heterogeneous phenotypes of expression of the NKB1 natural killer cell class I receptor among individuals of different human histocompatibility leukocyte antigens types appear genetically regulated, but not linked to major histocompatibililty complex haplotype.

1996 ◽  
Vol 183 (4) ◽  
pp. 1817-1827 ◽  
Author(s):  
J E Gumperz ◽  
N M Valiante ◽  
P Parham ◽  
L L Lanier ◽  
D Tyan
Keyword(s):  
T Cells ◽  
Cell Surface ◽  
Nk Cells ◽  
Natural Killer ◽  
Killer Cell ◽  
Peripheral Blood Lymphocytes ◽  
Class I ◽  
Cell Surface Expression ◽  
Target Cells ◽  
Hla Type

Natural killer (NK) cells that express the NKB1 receptor are inhibited from killing target cells that possess human histocompatibility leukocyte antigen (HLA) B molecules bearing the Bw4 serological epitope. To investigate whether NKB1 expression is affected by HLA type, peripheral blood lymphocytes of 203 HLA-typed donors were examined. Most donors had a single population of NKB1+ cells, but some had two populations expressing different cell surface levels of NKB1, and others had no detectable NKB1+ cells. Among the donors expressing NKB1, both the relative abundance of NKB1+ NK cells and their level of cell surface expression varied substantially. The percentage of NKB1+ NK cells ranged from 0 to &gt;75% (mean 14.7%), and the mean fluorescence of the positive population varied over three orders of magnitude. For each donor, the small percentage of T cells expressing NKB1 (usually &lt;2%), had a pattern of expression mirroring that of the NK cells. NKB1 expression by NK and T cells remained stable over the 2-yr period that five donors were tested. Patterns of NKB1 expression were not associated with Bw4 or Bw6 serotype of the donor or with the presence of any individual HLA-A or -B antigens. Cells expressing NKB1 are often found in donors who do not possess an appropriate class I ligand, and can be absent in those who express Bw4+ HLA-B antigens. Family studies further suggested that the phenotype of NKB1 expression is inherited but not HLA linked. Whereas identical twins show matching patterns of NKB1 expression, HLA-identical siblings can differ in NKB1 expression, and conversely, HLA-disparate siblings can be similar. Thus NKB1 expression phenotypes are tightly regulated and extremely heterogeneous, but not correlated with HLA type.

scholarly journals The Bw4 public epitope of HLA-B molecules confers reactivity with natural killer cell clones that express NKB1, a putative HLA receptor.

1995 ◽  
Vol 181 (3) ◽  
pp. 1133-1144 ◽  
Author(s):  
J E Gumperz ◽  
V Litwin ◽  
J H Phillips ◽  
L L Lanier ◽  
P Parham
Keyword(s):  
Monoclonal Antibody ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Inhibitory Effect ◽  
Glycosylation Site ◽  
Class I ◽  
Target Cells ◽  
Cell Clones

Although inhibition of natural killer (NK) cell-mediated lysis by the class I HLA molecules of target cells is an established phenomenon, knowledge of the features of class I molecules which induce this effect remains rudimentary. Using class I alleles HLA-B*1502 and B*1513 which differ only at residues 77-83 which define the Bw4 and Bw6 serological epitopes, we tested the hypothesis that the presence of the Bw4 epitope on class I molecules determines recognition by NKB1+ NK cells. HLA-B*1513 possesses the Bw4 epitope, whereas B*1502 has the Bw6 epitope. Lysis by NKB1+ NK cell clones of transfected target cells expressing B*1513 as the only HLA-A, -B, or -C molecule was inhibited, whereas killing of transfectants expressing B*1502 was not. Addition of an an anti-NKB1 monoclonal antibody reconstituted lysis of the targets expressing B*1513, but did not affect killing of targets bearing B*1502. The inhibitory effect of B*1513 could be similarly prevented by the addition of an anti-class I monoclonal antibody. These results show that the presence of the Bw4 epitope influences recognition of HLA-B molecules by NK cells that express NKB1, and suggest that the NKB1 molecule may act as a receptor for Bw4+ HLA-B alleles. Sequences outside of the Bw4 region must also affect recognition by NKB1+ NK cells, because lysis of transfectants expressing HLA-A*2403 or A*2501, which possess the Bw4 epitope but are in other ways substantially different from HLA-B molecules, was not increased by addition of the anti-NKB1 antibody. Asparagine 86, the single site of N-linked glycosylation on class I molecules, is in close proximity to the Bw4/Bw6 region. The glycosylation site of the Bw4-positive molecule B*5801 was mutated, and the mutant molecules tested for inhibition of NKB1+ NK cells. Inhibition that could be reversed by addition of the anti-NKB1 monoclonal antibody was observed, showing the presence of the carbohydrate moiety is not essential for class I recognition by NKB1+ NK cell clones.

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