scholarly journals Coexistence of inhibitory and activating killer-cell immunoglobulin-like receptors to the same cognate HLA-C2 and Bw4 ligands confer breast cancer risk

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elham Ashouri ◽  
Karan Rajalingam ◽  
Shaghik Barani ◽  
Shirin Farjadian ◽  
Abbas Ghaderi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Cancer ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Risk Scores ◽  
Hla Ligands ◽  
Nk Cytotoxicity

AbstractHuman leukocyte antigen (HLA) class I-specific killer-cell immunoglobulin-like receptors (KIR) regulate natural killer (NK) cell function in eliminating malignancy. Breast cancer (BC) patients exhibit reduced NK-cytotoxicity in peripheral blood. To test the hypothesis that certain KIR-HLA combinations impairing NK-cytotoxicity predispose to BC risk, we analyzed KIR and HLA polymorphisms in 162 women with BC and 278 controls. KIR-Bx genotypes increased significantly in BC than controls (83.3% vs. 71.9%, OR 1.95), and the increase was more pronounced in advanced-cancer (OR 5.3). No difference was observed with inhibitory KIR (iKIR) and HLA-ligand combinations. The activating KIR (aKIR) and HLA-ligand combinations, 2DS1 + C2 (OR 2.98) and 3DS1 + Bw4 (OR 2.6), were significantly increased in advanced-BC. All patients with advanced-cancer carrying 2DS1 + C2 or 3DS1 + Bw4 also have their iKIR counterparts 2DL1 and 3DL1, respectively. Contrarily, the 2DL1 + C2 and 3DL1 + Bw4 pairs without their aKIR counterparts are significantly higher in controls. These data suggest that NK cells expressing iKIR to the cognate HLA-ligands in the absence of putative aKIR counterpart are instrumental in antitumor response. These data provide a new framework for improving the utility of genetic risk scores for individualized surveillance.

scholarly journals The molecular basis of how buried human leukocyte antigen polymorphism modulates natural killer cell function

2020 ◽  
Vol 117 (21) ◽  
pp. 11636-11647 ◽  
Author(s):  
Philippa M. Saunders ◽  
Bruce J. MacLachlan ◽  
Phillip Pymm ◽  
Patricia T. Illing ◽  
Yuanchen Deng ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Natural Killer ◽  
Nk Cell ◽  
Killer Cell ◽  
Peptide Binding ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Cell Recognition ◽  
Leukocyte Antigen ◽  
Binding Cleft

Micropolymorphisms within human leukocyte antigen (HLA) class I molecules can change the architecture of the peptide-binding cleft, leading to differences in peptide presentation and T cell recognition. The impact of such HLA variation on natural killer (NK) cell recognition remains unclear. Given the differential association of HLA-B*57:01 and HLA-B*57:03 with the control of HIV, recognition of these HLA-B57 allomorphs by the killer cell immunoglobulin-like receptor (KIR) 3DL1 was compared. Despite differing by only two polymorphic residues, both buried within the peptide-binding cleft, HLA-B*57:01 more potently inhibited NK cell activation. Direct-binding studies showed KIR3DL1 to preferentially recognize HLA-B*57:01, particularly when presenting peptides with positively charged position (P)Ω-2 residues. In HLA-B*57:01, charged PΩ-2 residues were oriented toward the peptide-binding cleft and away from KIR3DL1. In HLA-B*57:03, the charged PΩ-2 residues protruded out from the cleft and directly impacted KIR3DL1 engagement. Accordingly, KIR3DL1 recognition of HLA class I ligands is modulated by both the peptide sequence and conformation, as determined by the HLA polymorphic framework, providing a rationale for understanding differences in clinical associations.

scholarly journals ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Silvia D’Amico ◽  
Valerio D’Alicandro ◽  
Mirco Compagnone ◽  
Patrizia Tempora ◽  
Giusy Guida ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Subset ◽  
Human Tumor ◽  
Hla Class I ◽  
Class I ◽  
Pharmacological Inhibition ◽  
Mhc Class I Molecules

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

scholarly journals The Emerging Role of HLA-E-Restricted CD8+T Lymphocytes in the Adaptive Immune Response to Pathogens and Tumors

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Gabriella Pietra ◽  
Chiara Romagnani ◽  
Claudia Manzini ◽  
Lorenzo Moretta ◽  
Maria Cristina Mingari
Keyword(s):  
Cell Function ◽  
Nk Cell ◽  
Adaptive Immune Response ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Cell Receptor ◽  
Class I ◽  
Mhc Class I Molecule ◽  
Associated Proteins ◽  
Acquired Immune Responses

Human leukocyte antigen (HLA)-E is a nonclassical major histocompatibility complex (MHC) class I molecule of limited sequence variability that is expressed by most tissues albeit at low levels. HLA-E has been first described as the ligand of CD94/NKG2 receptors expressed mainly by natural killer (NK) cells, thus confining its role to the regulation of NK-cell function. However, recent evidences obtained by our and other groups indicate that HLA-E complexed with peptides can interact withαβT-cell receptor (TCR) expressed on CD8+T cells. Although, HLA-E displays a selective preference for nonameric peptides, derived from the leader sequence of various HLA class I alleles, several reports indicate that it can present also “noncanonical” peptides derived from both stress-related and pathogen-associated proteins. Because HLA-E displays binding specificity for innate CD94/NKG2 receptors, as well as all the features of an antigen-presenting molecule, its role in both natural and acquired immune responses has recently been re-evaluated.

Neonatal NK-cell repertoires are functionally, but not structurally, biased toward recognition of self HLA class I

Blood ◽  
2011 ◽  
Vol 117 (19) ◽  
pp. 5152-5156 ◽  
Author(s):  
Kathrin Schönberg ◽  
Johannes C. Fischer ◽  
Gesine Kögler ◽  
Markus Uhrberg
Keyword(s):  
Nk Cells ◽  
Cytokine Production ◽  
Nk Cell ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Class I ◽  
Structural Adaptation ◽  
Leukocyte Antigen ◽  
Kir Receptors

Abstract Human natural killer (NK)–cell repertoires are biased toward more frequent expression of inhibitory killer cell Ig-like receptor (KIR) receptors for self-human leukocyte antigen (HLA) class I. Moreover, only those NK cells that express cognate receptors for self are fully functional in terms of cytotoxicity and cytokine production. It is so far unknown whether functional education and structural adaptation to HLA class I are implemented during NK-cell development and whether both processes are mechanistically connected. Here we show that NK-cell repertoires in cord blood are not yet shaped toward increased clonal frequencies of KIR for self-HLA class I as determined for the 3 major KIR ligands C1, C2, and Bw4. Nonetheless, neonatal NK cells expressing cognate KIR exhibited enhanced effector function on the level of degranulation and cytokine production. The study suggests that functional education of cognate KIR by self-HLA class I precedes structural adaptation of KIR repertoires and that both processes are not directly linked to each other.

scholarly journals HLA Alleles and KIR Genes in Romanian Patients with Chronic Hepatitis C

2020 ◽  
Author(s):  
Larisa Ursu ◽  
Bogdan Calenic ◽  
Mircea Diculescu ◽  
Alina Dima ◽  
Ileana Constantinescu
Keyword(s):  
Hepatitis C ◽  
Nk Cells ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Hcv Infection ◽  
Hla Alleles ◽  
Kir Genes ◽  
Hla Ligands ◽  
Chronic Hcv

Background and Aims: The role of natural killer (NK) cells in the defense against hepatitis C virus (HCV) infection involve both innate and adaptive immunity. NK cells express a large panel of inhibitory and activating receptors who bind human leukocyte antigen (HLA) class I receptors. Killer cell immunoglobulin-like receptors (KIRs) are the most polymorphic of these receptors being encoded by genes distributed differently in unrelated individuals. The aim of this study was to look at the immune response in chronic HCV patients by assessing NK-KIR genes and their corresponding HLA ligands. Methods: We genotyped 127 chronically HCV-infected patients and 130 non-infected healthy individuals for both KIR genes and their HLA ligands. The HLA-A, HLA-B, HLA-C genotypes were analyzed using polymerase chain reaction high-resolution typing. Results: KIR2DL3, KIR2DL5, KIR2DS4 norm, KIR3DL3, KIR2DP1, KIR3DP1 genes were significantly increased in the HCV group compared to healthy individual. Analysis of various HLA haplotypes revealed different HLA alleles associated with increased susceptibility to HCV infection. Thus, HLA A*23:01 was more frequent in the patients’ group than in the controls (p=0.030). At the same time HLA B*44:02 and C*04:02 were significantly elevated in HCV-positive patients (p=0.008 and respectively p= 0.007). Conclusions: These results suggest that the expression of KIR2DL3, KIR2DL5, KIR2DS4 norm, KIR3DL3 genes and the association with HLA alleles such as HLA A*23:01, B*44:02, C*04:02 may increase the patient susceptibility to chronic HCV infection.

scholarly journals Successful Treatment of Pediatric Refractory/Relapsed AML with KIR-Ligand-Mismatched Cord Blood Transplant after FLAG-IDA Reinduction Therapy with or without the GO Regimen

2020 ◽  
Vol 2020 ◽  
pp. 1-4
Author(s):  
Daisuke Toyama ◽  
Ryosuke Matsuno ◽  
Yumiko Sugishita ◽  
Ryota Kaneko ◽  
Naoko Okamoto ◽  
...  
Keyword(s):  
Cord Blood ◽  
Nk Cells ◽  
Pediatric Patients ◽  
Combined Treatment ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Gemtuzumab Ozogamicin ◽  
Cord Blood Transplant ◽  
Hla Ligands

Prognosis in pediatric patients with refractory/relapsed acute myeloid leukemia (AML) is grim, and there is no standard treatment for such patients. Combined treatment with intensive chemotherapy and gemtuzumab ozogamicin (GO), a monoclonal anti-CD33 antibody conjugated with calicheamicin, is useful as reinduction therapy in refractory/relapsed AML. Here, we describe three cases of pediatric refractory/relapsed AML that were successfully managed with FLAG-IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin), with or without GO, as reinduction therapy before a KIR-ligand-mismatched cord blood transplant. This strategy relies on the fact that killer cell immunoglobulin-like receptors (KIR) on cord blood natural killer (NK) cells recognize human leukocyte antigen (HLA) class I alleles, and that donor KIR-ligand incompatibility may be associated with lower incidence of relapse and improved survival in AML, as cells that lack these inhibitory HLA ligands can activate NK cells. All three patients are currently alive and have been disease-free for 24–65 months, although one patient developed severe sinusoidal obstructive syndrome (SOS). Thus, our strategy can result in excellent outcomes in pediatric patients with refractory/relapsed AML.

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.

Abstract WP319: miRNA Screening of Natural Killer Cell Identifies miR-1224 as a Post-Transcriptional Regulator of NK Cell Function After Ischemic Stroke

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Yan Feng ◽  
Hui Zhao ◽  
Fu-Dong Shi ◽  
Weina Jin
Keyword(s):  
Ischemic Stroke ◽  
Cerebral Ischemia ◽  
Nk Cells ◽  
Expression Profile ◽  
Mirna Expression ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Mirna Expression Profile ◽  
Control Group

Objectives: To screen miRNA profile of peripheral NK cells in ischemic stroke mouse model and investigate a most promising candidate (miR-1224) for post-transcriptional regulation of NK cell function after ischemic stroke. Methods: Mice were subjected to a 60 min focal cerebral ischemia produced by transient intraluminal occlusion of MCAO. For NK cell isolation, cell suspensions from the spleens after reperfusion were enriched for NK cells using magnetic-bead sorting system after staining with anti-NK1.1 microbeads. The nCounter Mouse miRNA array was used to analyze miRNA expression profile in splenic NK cells over the time course of experimental ischemic stroke. Based on the miRNA data, we further in vitro modulated miR-1224 in NK cells using mimics or inhibitor, then injected i.v into Rag2-/-γc-/- recipient mice. Neurological function score was compared and spontaneous infection was assessed by pulmonary bacteria colony culture, and changes in potential signaling pathway (SP1/TNF-α) were verified by rt-PCR and western blot. Results: Through miRNA expression profile analysis, we have identified significant changes at each time point in peripheral NK cells after cerebral ischemia. Among all screened miRNA, miR-1224 remarkably increased in MCAO group, which was verified by PCR. Then isolated NK cells treated with mimics or inhibitors, were transferred to Rag2-/-γc-/- recipient mice. Compared with WT mice, Rag2-/-γc-/- mice with miR-1224 inhibitor exhibited increased NK cell number, enhanced NK cell activation/cytotoxicity feature, as well as better neurological behaviors and reduced pulmonary infection after MCAO. Moreover, compared with the control group, NK cells with miR-1224 inhibitor showed significantly increased SP1 gene and protein phosphorylation. As SP1 gene is one of the potential targets of miR-1224, this study suggests that miR-1224 may regulate NK cell function after MCAO, which is associated with SP1 pathway. Conclusion: The miRNA profiling of splenic NK cells provided insight into the functional mechanism and signaling pathways underlying the distinct organ-specific NK cell properties, which will contribute to the better understanding of NK cell mediated immune-response in relation to different stages of stroke.

scholarly journals Genomic Risk Factors Driving Immune-Mediated Delayed Drug Hypersensitivity Reactions

2021 ◽  
Vol 12 ◽  
Author(s):  
Yueran Li ◽  
Pooja Deshpande ◽  
Rebecca J. Hertzman ◽  
Amy M. Palubinsky ◽  
Andrew Gibson ◽  
...  
Keyword(s):  
T Cell ◽  
Predictive Value ◽  
Large Scale ◽  
Drug Hypersensitivity ◽  
Killer Cell ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Therapeutic Interventions ◽  
Hypersensitivity Reactions ◽  
Prediction And Prevention

Adverse drug reactions (ADRs) remain associated with significant mortality. Delayed hypersensitivity reactions (DHRs) that occur greater than 6 h following drug administration are T-cell mediated with many severe DHRs now associated with human leukocyte antigen (HLA) risk alleles, opening pathways for clinical prediction and prevention. However, incomplete negative predictive value (NPV), low positive predictive value (PPV), and a large number needed to test (NNT) to prevent one case have practically prevented large-scale and cost-effective screening implementation. Additional factors outside of HLA contributing to risk of severe T-cell-mediated DHRs include variation in drug metabolism, T-cell receptor (TCR) specificity, and, most recently, HLA-presented immunopeptidome-processing efficiencies via endoplasmic reticulum aminopeptidase (ERAP). Active research continues toward identification of other highly polymorphic factors likely to impose risk. These include those previously associated with T-cell-mediated HLA-associated infectious or auto-immune disease such as Killer cell immunoglobulin-like receptors (KIR), epistatically linked with HLA class I to regulate NK- and T-cell-mediated cytotoxic degranulation, and co-inhibitory signaling pathways for which therapeutic blockade in cancer immunotherapy is now associated with an increased incidence of DHRs. As such, the field now recognizes that susceptibility is not simply a static product of genetics but that individuals may experience dynamic risk, skewed toward immune activation through therapeutic interventions and epigenetic modifications driven by ecological exposures. This review provides an updated overview of current and proposed genetic factors thought to predispose risk for severe T-cell-mediated DHRs.

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