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Jost S, Reeves RK. Elephant in the room: natural killer cells don't forget HIV either. Curr Opin HIV AIDS 2025; 20:109-116. [PMID: 39773904 PMCID: PMC11802307 DOI: 10.1097/coh.0000000000000909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
PURPOSE OF REVIEW Like elephants (and T cells), accumulating evidence suggest natural killer (NK) cells never forget. The description of adaptive or memory NK cells, which can be induced by HIV/SIV infections and vaccines and associated with protective effects in persons with HIV (PWH), has dramatically increased the interest in leveraging NK cells to prevent HIV infection or suppress HIV reservoirs. However, harnessing their full antiviral potential has been hindered by an incomplete understanding of mechanisms underlying adaptive NK cell development and infected cell recognition. Herein, we outline the main discoveries around the adaptive functions of NK cells, with a focus on their involvement in HIV infection. RECENT FINDINGS NK cells with diverse adaptive capabilities, including antigen-specific memory, cytokine-induced and CMV-driven adaptive subsets, likely all play a role in HIV infection. Importantly, true antigen-specific memory NK cells have been identified that mediate recall responses against multiple infectious agents such as HIV, influenza, and SARS-CoV-2. The NKG2C receptor is pivotal for certain adaptive NK cell subsets, as it marks a population with enhanced antibody-dependent functions and has been described as the main receptor mediating antigen-specific responses via recognition of viral peptides presented by HLA-E. SUMMARY Antiviral functions of adaptive/memory NK cells have tremendous, but as of yet, untapped potential to be harnessed for vaccine design, curative, or other therapeutic interventions against HIV.
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Affiliation(s)
- Stephanie Jost
- Division of Innate and Comparative Immunology, Center for Human Systems Immunology, Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA
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2
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Gillespie GM, Quastel MN, McMichael AJ. HLA-E: Immune Receptor Functional Mechanisms Revealed by Structural Studies. Immunol Rev 2025; 329:e13434. [PMID: 39753525 PMCID: PMC11698700 DOI: 10.1111/imr.13434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 12/10/2024] [Indexed: 01/06/2025]
Abstract
HLA-E is a nonclassical, nonpolymorphic, class Ib HLA molecule. Its primary function is to present a conserved nonamer peptide, termed VL9, derived from the signal sequence of classical MHC molecules to the NKG2x-CD94 receptors on NK cells and a subset of T lymphocytes. These receptors regulate the function of NK cells, and the importance of this role, which is conserved across mammalian species, probably accounts for the lack of genetic polymorphism. A second minor function is to present other, weaker binding, pathogen-derived peptides to T lymphocytes. Most of these peptides bind suboptimally to HLA-E, but this binding appears to be enabled by the relative stability of peptide-free, but receptive, HLA-E-β2m complexes. This, in turn, may favor nonclassical antigen processing that may be associated with bacteria infected cells. This review explores how the structure of HLA-E, bound to different peptides and then to NKG2-CD94 or T-cell receptors, relates to HLA-E cell biology and immunology. A detailed understanding of this molecule could open up opportunities for development of universal T-cell and NK-cell-based immunotherapies.
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MESH Headings
- Humans
- Histocompatibility Antigens Class I/metabolism
- Histocompatibility Antigens Class I/immunology
- Histocompatibility Antigens Class I/chemistry
- Animals
- HLA-E Antigens
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- Protein Binding
- Antigen Presentation
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
- Receptors, Immunologic/metabolism
- Receptors, Immunologic/chemistry
- NK Cell Lectin-Like Receptor Subfamily C/metabolism
- Structure-Activity Relationship
- Peptides/chemistry
- Peptides/immunology
- Peptides/metabolism
- NK Cell Lectin-Like Receptor Subfamily D/metabolism
- NK Cell Lectin-Like Receptor Subfamily D/chemistry
- NK Cell Lectin-Like Receptor Subfamily D/immunology
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Antigen, T-Cell/immunology
- Receptors, Antigen, T-Cell/chemistry
- Protein Conformation
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Affiliation(s)
| | - Max N. Quastel
- Nuffield Department of Medicine, Center for Immuno‐OncologyUniversity of OxfordOxfordUK
| | - Andrew J. McMichael
- Nuffield Department of Medicine, Center for Immuno‐OncologyUniversity of OxfordOxfordUK
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3
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Murugesan G, Paterson RL, Kulkarni R, Ilkow V, Suckling RJ, Connolly MM, Karuppiah V, Pengelly R, Jadhav A, Donoso J, Heunis T, Bunjobpol W, Philips G, Ololade K, Kay D, Sarkar A, Barber C, Raj R, Perot C, Grant T, Treveil A, Walker A, Dembek M, Gibbs-Howe D, Hock M, Carreira RJ, Atkin KE, Dorrell L, Knox A, Leonard S, Salio M, Godinho LF. Viral sequence determines HLA-E-restricted T cell recognition of hepatitis B surface antigen. Nat Commun 2024; 15:10126. [PMID: 39578466 PMCID: PMC11584656 DOI: 10.1038/s41467-024-54378-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 11/08/2024] [Indexed: 11/24/2024] Open
Abstract
The non-polymorphic HLA-E molecule offers opportunities for new universal immunotherapeutic approaches to chronic infectious diseases. Chronic Hepatitis B virus (HBV) infection is driven in part by T cell dysfunction due to elevated levels of the HBV envelope (Env) protein hepatitis B surface antigen (HBsAg). Here we report the characterization of three genotypic variants of an HLA-E-binding HBsAg peptide, Env371-379, identified through bioinformatic predictions and verified by biochemical and cellular assays. Using a soluble affinity-enhanced T cell receptor (TCR) (a09b08)-anti-CD3 bispecific molecule to probe HLA-E presentation of the Env371-379 peptides, we demonstrate that only the most stable Env371-379 variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env371-379 L6I-specific CD8+ T cells are detectable in HBV-naïve donors and people with chronic HBV after in vitro priming. In conclusion, we provide evidence for HLA-E-mediated HBV Env peptide presentation, and highlight the effect of viral mutations on the stability and targetability of pHLA-E molecules.
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Affiliation(s)
| | | | - Rakesh Kulkarni
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Veronica Ilkow
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Mary M Connolly
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Robert Pengelly
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Archana Jadhav
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Jose Donoso
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Tiaan Heunis
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Gwilym Philips
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Kafayat Ololade
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Daniel Kay
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Anshuk Sarkar
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Claire Barber
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Ritu Raj
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Carole Perot
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Tressan Grant
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Agatha Treveil
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Andrew Walker
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Marcin Dembek
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Dawn Gibbs-Howe
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Miriam Hock
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | | | - Kate E Atkin
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Lucy Dorrell
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Andrew Knox
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Sarah Leonard
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Mariolina Salio
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK
| | - Luis F Godinho
- Immunocore Ltd, 92 Park Drive, Abingdon, Oxfordshire, OX14 4RY, UK.
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4
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Le Luduec JB, Kontopoulos T, Panjwani MK, Sottile R, Liu H, Schäfer G, Massalski C, Lange V, Hsu KC. Polygenic polymorphism is associated with NKG2A repertoire and influences lymphocyte phenotype and function. Blood Adv 2024; 8:5382-5399. [PMID: 39158076 PMCID: PMC11568789 DOI: 10.1182/bloodadvances.2024013508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 07/10/2024] [Accepted: 07/27/2024] [Indexed: 08/20/2024] Open
Abstract
ABSTRACT CD94/NKG2A is a heterodimeric receptor commonly found on natural killer (NK) and T cells, and its interaction with its ligand HLA-E on adjacent cells leads to inhibitory signaling and cell suppression. We have identified several killer cell lectin-like receptor (KLR)C1 (NKG2A) single nucleotide polymorphisms (SNPs) that are associated with NKG2A expression on NK cells, CD8+ T cells, and Vγ9/Vδ2+ T cells. Additionally, due to strong linkage disequilibrium, polymorphisms in KLRC2 (NKG2C) and KLRK1 (NKG2D) are also associated with NKG2A surface density and frequency. NKG2A surface expression correlates with single-cell NK responsiveness, and NKG2A+ NK cell frequency is associated with total NK repertoire response and inhibitability, making the identification of SNPs responsible for expression and frequency important for predicting the innate immune response. Because HLA-E expression is dependent on HLA class I signal peptides, we analyzed the relationship between peptide abundance and HLA-E expression levels. Our findings revealed a strong association between peptide availability and HLA-E expression. We identified the HLA-C killer immunoglobulin-like receptor ligand epitope as a predictive marker for HLA-ABC expression, with the HLA-C1 epitope associated with high HLA-E expression and the HLA-C2 epitope associated with low HLA-E expression. The relationship between HLA-C epitopes and HLA-E expression was independent of HLA-E allotypes and HLA-B leader peptides. Although HLA-E expression showed no significant influence on NKG2A-mediated NK education, it did affect NK cell inhibition. In summary, these findings underscore the importance of NKG2A SNPs and HLA-C epitopes as predictive markers of NK cell phenotype and function and should be evaluated as prognostic markers for diseases that express high levels of HLA-E.
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Affiliation(s)
- Jean-Benoît Le Luduec
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Theodota Kontopoulos
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - M Kazim Panjwani
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Rosa Sottile
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
- Humanitas Clinical and Research Center, Pieve Emanuele, Italy
| | - Hongtao Liu
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Gesine Schäfer
- Genotyping Laboratory, Deutsche Knochenmarkspenderdatei Life Science Lab, Dresden, Germany
| | - Carolin Massalski
- Genotyping Laboratory, Deutsche Knochenmarkspenderdatei Life Science Lab, Dresden, Germany
| | - Vinzenz Lange
- Genotyping Laboratory, Deutsche Knochenmarkspenderdatei Life Science Lab, Dresden, Germany
| | - Katharine C Hsu
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Weill Cornell Medical College, New York, NY
- Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY
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5
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Rohn H, Rebmann V. Is HLA-E with its receptors an immune checkpoint or an antigenic determinant in allo-HCT? Best Pract Res Clin Haematol 2024; 37:101560. [PMID: 39098806 DOI: 10.1016/j.beha.2024.101560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 05/26/2024] [Accepted: 06/27/2024] [Indexed: 08/06/2024]
Abstract
Hematopoietic cell transplantation (HCT) represents a potentially curative therapeutic approach for various hematologic and non-hematologic malignancies. Human leukocyte antigen (HLA) matching is still the central selection criterion for HCT donors. Nevertheless, post-transplant complications, in particular graft-versus-host disease (GvHD), relapse of disease and infectious complications, represent a major challenge and contribute significantly to morbidity and mortality. Recently, non-classical HLA class I molecules, especially HLA-E, have gained increasing attention in the context of allogeneic HCT. This review aims to summarize the latest findings on the immunomodulatory role of HLA-E, which serves as a ligand for receptors of the innate and adaptive immune system. In particular, we aim to elucidate how (i) polymorphisms within HLA-E, (ii) the NKG2A/C axis and (iii) the repertoire of peptides presented by HLA-E jointly influence the functionality of immune effector cells. Understanding this intricate network of interactions is crucial as it significantly affects NK and T cell responses and thus clinical outcomes after HCT.
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Affiliation(s)
- Hana Rohn
- Department of Infectious Diseases, West German Centre of Infectious Diseases, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
| | - Vera Rebmann
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
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Torki E, Gharezade A, Doroudchi M, Sheikhi S, Mansury D, Sullman MJM, Fouladseresht H. The kinetics of inhibitory immune checkpoints during and post-COVID-19: the knowns and unknowns. Clin Exp Med 2023; 23:3299-3319. [PMID: 37697158 DOI: 10.1007/s10238-023-01188-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 08/31/2023] [Indexed: 09/13/2023]
Abstract
The immune system is tightly regulated to prevent immune reactions to self-antigens and to avoid excessive immune responses during and after challenges from non-self-antigens. Inhibitory immune checkpoints (IICPs), as the major regulators of immune system responses, are extremely important for maintaining the homeostasis of cells and tissues. However, the high and sustained co-expression of IICPs in chronic infections, under persistent antigenic stimulations, results in reduced immune cell functioning and more severe and prolonged disease complications. Furthermore, IICPs-mediated interactions can be hijacked by pathogens in order to evade immune induction or effector mechanisms. Therefore, IICPs can be potential targets for the prognosis and treatment of chronic infectious diseases. This is especially the case with regards to the most challenging infectious disease of recent times, coronavirus disease-2019 (COVID-19), whose long-term complications can persist long after recovery. This article reviews the current knowledge about the kinetics and functioning of the IICPs during and post-COVID-19.
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Affiliation(s)
- Ensiye Torki
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arezou Gharezade
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mehrnoosh Doroudchi
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shima Sheikhi
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Davood Mansury
- Department of Microbiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mark J M Sullman
- Department of Life and Health Sciences, University of Nicosia, Nicosia, Cyprus
- Department of Social Sciences, University of Nicosia, Nicosia, Cyprus
| | - Hamed Fouladseresht
- Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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7
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Wang X, Xiong H, Ning Z. Implications of NKG2A in immunity and immune-mediated diseases. Front Immunol 2022; 13:960852. [PMID: 36032104 PMCID: PMC9399941 DOI: 10.3389/fimmu.2022.960852] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 07/21/2022] [Indexed: 11/22/2022] Open
Abstract
In recent studies, NKG2A is revealed to be a key immune checkpoint for both natural killer (NK) cells and CD8+ T cells. It form heterodimer receptors with CD94, and targets the peptide-presenting human leukocyte antigen-E (HLA-E) molecules. Upon crosslinking, NKG2A/CD94 delivers inhibitory signals for NK cells and CD8+ T cells, while blocking NKG2A can effectively unleash functions of these cytotoxic lymphocytes. The interaction between NKG2A and HLA-E contributes to tumor immune escape, and NKG2A-mediated mechanisms are currently being exploited to develop potential antitumor therapeutic strategies. In addition, growing evidence shows that NKG2A also plays important roles in other immune-related diseases including viral infections, autoimmune diseases, inflammatory diseases, parasite infections and transplant rejection. Therefore, the current work focuses on describing the effect of NKG2A on immune regulation and exploring its potential role in immune-mediated disorders.
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Affiliation(s)
- Xiaotong Wang
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, China
| | - Huabao Xiong
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, China
- *Correspondence: Zhaochen Ning, ; Huabao Xiong,
| | - Zhaochen Ning
- Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, China
- Jining Key Laboratory of Immunology, Jining Medical University, Jining, China
- *Correspondence: Zhaochen Ning, ; Huabao Xiong,
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Hosseini E, Sarraf Kazerooni E, Azarkeivan A, Sharifi Z, Shahabi M, Ghasemzadeh M. HLA-E*01:01 allele is associated with better response to anti-HCV therapy while homozygous status for HLA-E*01:03 allele increases the resistance to anti-HCV treatments in frequently transfused thalassemia patients. Hum Immunol 2022; 83:556-563. [PMID: 35570067 DOI: 10.1016/j.humimm.2022.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 04/23/2022] [Accepted: 04/24/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND HLA-E binding to NKG2A/CD94 induces inhibitory signals that modulate NK cells cytotoxicity against infected targets. HCV-derived peptides stabilize HLA-E molecule that favours its higher expression. However, HLA-E stability and expression vary in different genotypes where the presence of HLA-E*01:03 allele is associated with higher HLA-E expression on targets that enhances NK cells inhibition and increases the chance of virus to escape from innate immune system. Here, we aimed to investigate whether HLA-E polymorphism affects HCV infection status or its treatment in major thalassemia patients who are more vulnerable to hepatitis C. METHODS AND MATERIALS Study included 89 cases of major thalassemia positive for HCV-antibody; of those 17 patients were negative for HCV-PCR (spontaneously cleared) and 72 patients were HCV-PCR positive (persistent hepatitis under different anti-viral treatment). 16 major thalassemia patients without hepatitis, negative for HCV-antibody were also considered as patients control group. Genomic DNAs extracted from whole bloods were genotyped for HLA-E locus using a sequence specific primer-PCR strategy. RESULTS In thalassemia patients, HLA-E*01:03 allele increased susceptibility to HCV infection [p = 0.02; 4.74(1.418-15.85)]. In addition, HLA-E*01:03/*01:03 genotype predicted more resistance to HCV treatment compared to other genotypes [p = 0.037; 3.5(1.1-11.4)]. In other words, we found that the presence of HLA-E*01:01 allele favors better response to anti-HCV therapy [p = 0.037; 3.5(1.1-11.4)]. CONCLUSION From a mechanistic point of view, the associations between HLA-E polymorphisms and susceptibility to HCV infection or its therapeutic resistance in thalassemia patients may suggest potential roles for the innate and adaptive immune responses to this infection, which are manifested by the acts of HLA-E - NKG2A/CD94 axis in the modulation of NK cell inhibitory function as well as HLA-E associated CD8+ T cell cytolytic activity against HCV, respectively. Notably, from a clinical point of view, paying attention to these associations may not only be useful in increasing the effectiveness of current anti-HCV regimens comprising direct acting antivirals (DAAs) in more complicated patients, but may also suggest antiviral prophylaxis for patients more vulnerable to HCV infection.
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Affiliation(s)
- Ehteramolsadat Hosseini
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Ehsan Sarraf Kazerooni
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Azita Azarkeivan
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran; Iranian Blood Transfusion Organization, Thalassemia Clinic, Tehran, Iran
| | - Zohreh Sharifi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Majid Shahabi
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Mehran Ghasemzadeh
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran.
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9
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Hammer Q, Dunst J, Christ W, Picarazzi F, Wendorff M, Momayyezi P, Huhn O, Netskar HK, Maleki KT, García M, Sekine T, Sohlberg E, Azzimato V, Aouadi M, Degenhardt F, Franke A, Spallotta F, Mori M, Michaëlsson J, Björkström NK, Rückert T, Romagnani C, Horowitz A, Klingström J, Ljunggren HG, Malmberg KJ. SARS-CoV-2 Nsp13 encodes for an HLA-E-stabilizing peptide that abrogates inhibition of NKG2A-expressing NK cells. Cell Rep 2022; 38:110503. [PMID: 35235832 PMCID: PMC8858686 DOI: 10.1016/j.celrep.2022.110503] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 01/12/2022] [Accepted: 02/15/2022] [Indexed: 01/08/2023] Open
Abstract
Natural killer (NK) cells are innate immune cells that contribute to host defense against virus infections. NK cells respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro and are activated in patients with acute coronavirus disease 2019 (COVID-19). However, by which mechanisms NK cells detect SARS-CoV-2-infected cells remains largely unknown. Here, we show that the Non-structural protein 13 of SARS-CoV-2 encodes for a peptide that is presented by human leukocyte antigen E (HLA-E). In contrast with self-peptides, the viral peptide prevents binding of HLA-E to the inhibitory receptor NKG2A, thereby rendering target cells susceptible to NK cell attack. In line with these observations, NKG2A-expressing NK cells are particularly activated in patients with COVID-19 and proficiently limit SARS-CoV-2 replication in infected lung epithelial cells in vitro. Thus, these data suggest that a viral peptide presented by HLA-E abrogates inhibition of NKG2A+ NK cells, resulting in missing self-recognition.
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Affiliation(s)
- Quirin Hammer
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
| | - Josefine Dunst
- Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden
| | - Wanda Christ
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Francesca Picarazzi
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Mareike Wendorff
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Pouria Momayyezi
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Oisín Huhn
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Herman K Netskar
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - Kimia T Maleki
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Marina García
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Takuya Sekine
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Ebba Sohlberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Valerio Azzimato
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Myriam Aouadi
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Frauke Degenhardt
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
| | - Francesco Spallotta
- Institute for Systems Analysis and Computer Science "A. Ruberti," National Research Council (IASI-CNR), Rome, Italy
| | - Mattia Mori
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Jakob Michaëlsson
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Niklas K Björkström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Timo Rückert
- Innate Immunity, Deutsches Rheuma-Forschungszentrum (DRFZ), Institute of the Leibniz Association, Berlin, Germany
| | - Chiara Romagnani
- Innate Immunity, Deutsches Rheuma-Forschungszentrum (DRFZ), Institute of the Leibniz Association, Berlin, Germany; Division of Gastroenterology, Infectiology and Rheumatology, Medical Department I, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Amir Horowitz
- Department of Oncological Sciences, Precision Immunology Institute, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jonas Klingström
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Hans-Gustaf Ljunggren
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden
| | - Karl-Johan Malmberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
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10
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Araújo RC, Bertol BC, César Dias F, Debortoli G, Almeida PH, Fernandes Souza F, Villanova MG, Ramalho LNZ, Candolo Martinelli AL, Cruz Castelli ÉD, Mendes Junior CT, Antonio Donadi E. HLA-E gene polymorphisms in chronic hepatitis C: Impact on HLA-E liver expression and disease severity. Hum Immunol 2021; 82:177-185. [PMID: 33597096 DOI: 10.1016/j.humimm.2021.01.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 01/04/2021] [Accepted: 01/28/2021] [Indexed: 10/22/2022]
Abstract
Hepatitis C virus usually produces chronic infection and liver damage. Considering that: i) the human leukocyte antigen-E (HLA-E) molecule may modulate the immune response, and ii) little is known about the role of HLA-E gene variability on chronic hepatitis C, we studied the impact of HLA-E polymorphisms on the magnitude of HLA-E liver expression and severity of hepatitis C. HLA-E variability was evaluated in terms of: i) single nucleotide polymorphism (SNP) alleles and genotypes along the gene (beginning of the promoter region, coding region and 3'UTR), and ii) ensemble of SNPs that defines the coding region alleles, considered individually or as genotypes. The comparisons of the HLA-E variation sites between patients and controls revealed no significant results. The HLA-E + 424 T > C (rs1059510), +756 G > A (rs1264457) and + 3777 G > A (rs1059655) variation sites and the HLA-E*01:01:01:01 and HLA-E*01:03:02:01 alleles, considered at single or double doses, were associated with the magnitude of HLA-E liver expression in Kupfer cell, steatosis, inflammatory activity and liver fibrosis. Although these associations were lost after corrections for multiple comparisons, these variable sites may propitiate biological clues for the understanding of the mechanisms associated with hepatitis C severity.
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Affiliation(s)
- Roberta Chaves Araújo
- Gastroenterology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, State of São Paulo, Brazil.
| | - Bruna Cristina Bertol
- Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, State of São Paulo, Brazil
| | - Fabricio César Dias
- Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, State of São Paulo, Brazil
| | - Guilherme Debortoli
- Department of Anthropology, University of Toronto at Mississauga, Mississauga, ON, Canada
| | - Patrícia Holanda Almeida
- Liver Transplant Department - Hospital Israelita Albert Einstein, 05652-900 São Paulo, State of São Paulo, Brazil
| | - Fernanda Fernandes Souza
- Gastroenterology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, State of São Paulo, Brazil
| | - Marcia Guimarães Villanova
- Gastroenterology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, State of São Paulo, Brazil
| | - Leandra Naira Zambelli Ramalho
- Pathology Department, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, State of São Paulo, Brazil
| | - Ana Lourdes Candolo Martinelli
- Gastroenterology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, State of São Paulo, Brazil
| | - Érick da Cruz Castelli
- Department of Pathology, School of Medicine. São Paulo State University, 18618-687 Botucatu, State of São Paulo, Brazil
| | - Celso Teixeira Mendes Junior
- Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14048-900 Ribeirão Preto, State of São Paulo, Brazil
| | - Eduardo Antonio Donadi
- Immunology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, State of São Paulo, Brazil
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11
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Walters LC, McMichael AJ, Gillespie GM. Detailed and atypical HLA-E peptide binding motifs revealed by a novel peptide exchange binding assay. Eur J Immunol 2020; 50:2075-2091. [PMID: 32716529 DOI: 10.1002/eji.202048719] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/19/2020] [Accepted: 07/23/2020] [Indexed: 11/05/2022]
Abstract
Diverse SIV and HIV epitopes that bind the rhesus homolog of HLA-E, Mamu-E, have recently been identified in SIVvaccine studies using a recombinant Rhesus cytomegalovirus (RhCMV 68-1) vector, where unprecedented protection against SIV challenge was achieved. Additionally, several Mycobacterial peptides identified both algorithmically and following elution from infected cells, are presented to CD8+ T cells by HLA-E in humans. Yet, a comparative and comprehensive analysis of relative HLA-E peptide binding strength via a reliable, high throughput in vitro assay is currently lacking. To address this, we developed and optimized a novel, highly sensitive peptide exchange ELISA-based assay that relatively quantitates peptide binding to HLA-E. Using this approach, we screened multiple peptides, including peptide panels derived from HIV, SIV, and Mtb predicted to bind HLA-E. Our results indicate that although HLA-E preferentially accommodates canonical MHC class I leader peptides, many non-canonical, sequence diverse, pathogen-derived peptides also bind HLA-E, albeit generally with lower relative binding strength. Additionally, our screens demonstrate that the majority of peptides tested, including some key Mtb and SIV epitopes that have been shown to elicit strong Mamu-E-restricted T cell responses, either bind HLA-E extremely weakly or give signals that are indistinguishable from the negative, peptide-free controls.
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Affiliation(s)
- Lucy C Walters
- Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Andrew J McMichael
- Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Geraldine M Gillespie
- Nuffield Department of Medicine Research Building, Roosevelt Drive, Nuffield Department of Medicine, University of Oxford, Oxford, UK
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12
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Hò GGT, Hiemisch W, Pich A, Behrens GMN, Blasczyk R, Bade-Doeding C. The Loss of HLA-F/KIR3DS1 Ligation Is Mediated by Hemoglobin Peptides. Int J Mol Sci 2020; 21:ijms21218012. [PMID: 33126487 PMCID: PMC7672607 DOI: 10.3390/ijms21218012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 10/16/2020] [Accepted: 10/21/2020] [Indexed: 12/27/2022] Open
Abstract
The human leukocyte antigen (HLA)-Ib molecule, HLA-F, is known as a CD4+ T-cell protein and mediator of HIV progression. While HLA-Ia molecules do not have the chance to select and present viral peptides for immune recognition due to protein downregulation, HLA-F is upregulated. Post HIV infection, HLA-F loses the affinity to its activating receptor KIR3DS1 on NK cells leading to progression of the HIV infection. Several studies aimed to solve the question of the biophysical interface between HLA ligands and their cognate receptors. It became clear that even an invariant HLA molecule can be structurally modified by the variability of the bound peptide. We recently discovered the ability of HLA-F to select and present peptides and the HLA-F allele-specific peptide selection from the proteomic content using soluble HLA (sHLA) technology and a sophisticated MS method. We established recombinant K562 cells that express membrane-bound HLA-F*01:01, 01:03 or 01:04 complexes. While a recombinant soluble form of KIR3DS1 did not bind to the peptide-HLA-F complexes, acid elution of the peptides resulted in the presentation of HLA-F open conformers, and the binding of the soluble KIR3DS1 receptor increased. We used CD4+/HIV− and CD4+/HIV+ cells and performed an MS proteome analysis. We could detect hemoglobin as significantly upregulated in CD4+ T-cells post HIV infection. The expression of cellular hemoglobin in nonerythroid cells has been described, yet HLA-Ib presentation of hemoglobin-derived peptides is novel. Peptide sequence analysis from HLA-F allelic variants featured hemoglobin peptides as dominant and shared. The reciprocal experiment of binding hemoglobin peptide fractions to the HLA-F open conformers resulted in significantly diminished receptor recognition. These results underpin the molecular involvement of HLA-F and its designated peptide ligand in HIV immune escape.
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Affiliation(s)
- Gia-Gia T. Hò
- Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; (G.-G.T.H.); (W.H.); (R.B.)
| | - Wiebke Hiemisch
- Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; (G.-G.T.H.); (W.H.); (R.B.)
| | - Andreas Pich
- Institute of Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany;
| | - Georg M. N. Behrens
- Department of Rheumatology and Immunology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany;
- German Center for Infections Research, partner site Hannover-Braunschweig, Inhoffenstraße 7, 38124 Braunschweig, Germany
| | - Rainer Blasczyk
- Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; (G.-G.T.H.); (W.H.); (R.B.)
| | - Christina Bade-Doeding
- Institute for Transfusion Medicine, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; (G.-G.T.H.); (W.H.); (R.B.)
- Correspondence: ; Tel.: +49-511-532-9744; Fax: +49-511-532-2079
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13
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Regulation of natural killer cells: analog peptide handshake goes digital. AIDS 2020; 34:1857-1858. [PMID: 32889856 DOI: 10.1097/qad.0000000000002657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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14
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Rosen HR, Golden-Mason L. Control of HCV Infection by Natural Killer Cells and Macrophages. Cold Spring Harb Perspect Med 2020; 10:a037101. [PMID: 31871225 PMCID: PMC7447067 DOI: 10.1101/cshperspect.a037101] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Host defense against invading pathogens within the liver is dominated by innate immunity. Natural killer (NK) cells have been implicated at all stages of hepatitis C virus (HCV) infection, from providing innate protection to contributing to treatment-induced clearance. Decreased NK cell levels, altered NK cell subset distribution, activation marker expression, and functional polarization toward a cytolytic phenotype are hallmarks of chronic HCV infection. Interferon α (IFN-α) is a potent activator of NK cells; therefore, it is not surprising that NK cell activation has been identified as a key factor associated with sustained virological response (SVR) to IFN-α-based therapies. Understanding the role of NK cells, macrophages, and other innate immune cells post-SVR remains paramount for prevention of disease pathogenesis and progression. Novel strategies to treat liver disease may be aimed at targeting these cells.
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Affiliation(s)
- Hugo R Rosen
- Department of Medicine, University of Southern California (USC), Los Angeles, California 90033, USA
- USC Research Center for Liver Diseases, Los Angeles, California 90033, USA
| | - Lucy Golden-Mason
- Department of Medicine, University of Southern California (USC), Los Angeles, California 90033, USA
- USC Research Center for Liver Diseases, Los Angeles, California 90033, USA
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15
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Abstract
The continuous interactions between host and pathogens during their coevolution have shaped both the immune system and the countermeasures used by pathogens. Natural killer (NK) cells are innate lymphocytes that are considered central players in the antiviral response. Not only do they express a variety of inhibitory and activating receptors to discriminate and eliminate target cells but they can also produce immunoregulatory cytokines to alert the immune system. Reciprocally, several unrelated viruses including cytomegalovirus, human immunodeficiency virus, influenza virus, and dengue virus have evolved a multitude of mechanisms to evade NK cell function, such as the targeting of pathways for NK cell receptors and their ligands, apoptosis, and cytokine-mediated signaling. The studies discussed in this article provide further insights into the antiviral function of NK cells and the pathways involved, their constituent proteins, and ways in which they could be manipulated for host benefit.
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Affiliation(s)
- Mathieu Mancini
- Department of Human Genetics, McGill University, Montreal, Quebec H3A 0C7, Canada;,
- McGill University Research Centre on Complex Traits, McGill University, Montreal, Quebec H3G 0B1, Canada
| | - Silvia M. Vidal
- Department of Human Genetics, McGill University, Montreal, Quebec H3A 0C7, Canada;,
- McGill University Research Centre on Complex Traits, McGill University, Montreal, Quebec H3G 0B1, Canada
- Department of Medicine, McGill University, Montreal, Quebec H4A 3J1, Canada
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16
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Njiomegnie GF, Read SA, Fewings N, George J, McKay F, Ahlenstiel G. Immunomodulation of the Natural Killer Cell Phenotype and Response during HCV Infection. J Clin Med 2020; 9:jcm9041030. [PMID: 32268490 PMCID: PMC7230811 DOI: 10.3390/jcm9041030] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Accepted: 03/30/2020] [Indexed: 12/15/2022] Open
Abstract
Hepatitis C virus (HCV) infection develops into chronic hepatitis in over two-thirds of acute infections. While current treatments with direct-acting antivirals (DAAs) achieve HCV eradication in >95% of cases, no vaccine is available and re-infection can readily occur. Natural killer (NK) cells represent a key cellular component of the innate immune system, participating in early defence against infectious diseases, viruses, and cancers. When acute infection becomes chronic, however, NK cell function is altered. This has been well studied in the context of HCV, where changes in frequency and distribution of NK cell populations have been reported. While activating receptors are downregulated on NK cells in both acute and chronic infection, NK cell inhibiting receptors are upregulated in chronic HCV infection, leading to altered NK cell responsiveness. Furthermore, chronic activation of NK cells following HCV infection contributes to liver inflammation and disease progression through enhanced cytotoxicity. Consequently, the NK immune response is a double-edged sword that is a significant component of the innate immune antiviral response, but persistent activation can drive tissue damage during chronic infection. This review will summarise the role of NK cells in HCV infection, and the changes that occur during HCV therapy.
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Affiliation(s)
- Gaitan Fabrice Njiomegnie
- Blacktown Clinical School and Research Centre, Western Sydney University, Blacktown 2148, NSW, Australia (S.A.R.)
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia
| | - Scott A. Read
- Blacktown Clinical School and Research Centre, Western Sydney University, Blacktown 2148, NSW, Australia (S.A.R.)
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia
- Blacktown Hospital, Blacktown 2148, NSW, Australia
| | - Nicole Fewings
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Westmead 2145, NSW, Australia
- Westmead Clinical School, University of Sydney, Westmead 2145, NSW, Australia
| | - Jacob George
- Blacktown Clinical School and Research Centre, Western Sydney University, Blacktown 2148, NSW, Australia (S.A.R.)
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia
- Westmead Clinical School, University of Sydney, Westmead 2145, NSW, Australia
- Westmead Hospital, Westmead 2145, NSW, Australia
| | - Fiona McKay
- Centre for Immunology and Allergy Research, Westmead Institute for Medical Research, Westmead 2145, NSW, Australia
- Westmead Clinical School, University of Sydney, Westmead 2145, NSW, Australia
| | - Golo Ahlenstiel
- Blacktown Clinical School and Research Centre, Western Sydney University, Blacktown 2148, NSW, Australia (S.A.R.)
- Storr Liver Centre, Westmead Institute for Medical Research, University of Sydney, Westmead 2145, NSW, Australia
- Blacktown Hospital, Blacktown 2148, NSW, Australia
- Westmead Clinical School, University of Sydney, Westmead 2145, NSW, Australia
- Correspondence: ; Tel.: +61-2-9851-6073
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17
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Grant EJ, Nguyen AT, Lobos CA, Szeto C, Chatzileontiadou DSM, Gras S. The unconventional role of HLA-E: The road less traveled. Mol Immunol 2020; 120:101-112. [PMID: 32113130 DOI: 10.1016/j.molimm.2020.02.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 02/16/2020] [Accepted: 02/18/2020] [Indexed: 12/14/2022]
Abstract
Histocompatibility Leukocyte Antigens, or HLAs, are one of the most polymorphic molecules in humans. This high degree of polymorphism endows HLA molecules with the ability to present a vast array of peptides, an essential trait for responding to ever-evolving pathogens. Unlike classical HLA molecules (HLA-Ia), some non-classical HLA-Ib molecules, including HLA-E, are almost monomorphic. Several studies show HLA-E can present self-peptides originating from the leader sequence of other HLA molecules, which signals to our immune system that the cell is healthy. Therefore, it was traditionally thought that the chief role of HLA-E in the body was in immune surveillance. However, there is emerging evidence that HLA-E is also able to present pathogen-derived peptides to the adaptive immune system, namely T cells, in a manner that is similar to classical HLA-Ia molecules. Here we describe the early findings of this less conventional role of HLA-E in the adaptive immune system and its importance for immunity.
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Affiliation(s)
- Emma J Grant
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Andrea T Nguyen
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Christian A Lobos
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Christopher Szeto
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Demetra S M Chatzileontiadou
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia
| | - Stephanie Gras
- Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
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18
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Ferrari C, Barili V, Varchetta S, Mondelli MU. Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis. THE LIVER 2020:821-850. [DOI: 10.1002/9781119436812.ch63] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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19
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Wyatt RC, Lanzoni G, Russell MA, Gerling I, Richardson SJ. What the HLA-I!-Classical and Non-classical HLA Class I and Their Potential Roles in Type 1 Diabetes. Curr Diab Rep 2019; 19:159. [PMID: 31820163 PMCID: PMC6901423 DOI: 10.1007/s11892-019-1245-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Hyperexpression of classical HLA class I (HLA-I) molecules in insulin-containing islets has become a widely accepted hallmark of type 1 diabetes pathology. In comparison, relatively little is known about the expression, function and role of non-classical subtypes of HLA-I. This review focuses on the current understanding of the non-classical HLA-I subtypes: HLA-E, HLA-F and HLA-G, within and outside the field of type 1 diabetes, and considers the possible impacts of these molecules on disease etiology. RECENT FINDINGS Evidence is growing to suggest that non-classical HLA-I proteins are upregulated, both at the RNA and protein levels in the pancreas of individuals with recent-onset type 1 diabetes. Moreover, associations between non-classical HLA-I genotypes and age at onset of type 1 diabetes have been reported in some studies. As with classical HLA-I, it is likely that hyperexpression of non-classical HLA-I is driven by the release of diffusible interferons by stressed β cells (potentially driven by viral infection) and exacerbated by release of cytokines from infiltrating immune cells. Non-classical HLA-I proteins predominantly (but not exclusively) transduce negative signals to immune cells infiltrating at the site of injury/inflammation. We propose a model in which the islet endocrine cells, through expression of non-classical HLA-I are fighting back against the infiltrating immune cells. By inhibiting the activity and function on NK, B and select T cells, the non-classical HLA-I, proteins will reduce the non-specific bystander effects of inflammation, while at the same time still allowing the targeted destruction of β cells by specific islet-reactive CD8+ T cells.
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Affiliation(s)
- Rebecca C. Wyatt
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter, EX2 5DW UK
| | - Giacomo Lanzoni
- Diabetes Research Institute, University of Miami – Miller School of Medicine, 1450 NW 10th Avenue, Miami, FL 33136 USA
- Department of Biochemistry and Molecular Biology, University of Miami – Miller School of Medicine, 1011 NW 15th Street, Miami, FL 33136 USA
| | - Mark A. Russell
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter, EX2 5DW UK
| | - Ivan Gerling
- Department of Medicine University of Tennessee Health Science Center and VA Medical Center Research Service, 1030 Jefferson Avenue, Memphis, TN 38128 USA
| | - Sarah J. Richardson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD Building, Barrack Road, Exeter, EX2 5DW UK
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20
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Immunological Dynamics Associated with Direct-Acting Antiviral Therapies in Naive and Experimented HCV Chronic-Infected Patients. Mediators Inflamm 2019; 2019:4738237. [PMID: 31780860 PMCID: PMC6875334 DOI: 10.1155/2019/4738237] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 08/09/2019] [Accepted: 09/04/2019] [Indexed: 02/06/2023] Open
Abstract
The therapeutic strategies used in the treatment of hepatitis C are essentially based on the combination of direct-acting antiviral agents (DAAs). This therapy has been shown to be very effective in relation to patient adherence to treatment and has shown high rates of sustained virological response (SVR). However, the immunological dynamics of patients infected with HCV is poorly understood. This fact led us to investigate the immune system of naive and experienced patients, who we followed before the therapy and three months after the end of treatment. In this study, 35 naive and experienced Brazilian patients with chronic hepatitis C and 50 healthy donors (HD group) were studied. The analysis of the soluble immunological biomarkers was performed using the flow cytometry methodology. The SVR rate was >90% among the 35 patients. Before treatment, correlations in the naive HCV group demonstrated a mix of inflammatory response occurring with moderate correlations between chemokines, inflammatory cytokines, and Th2 profile, with a strong regulation between IL-10 and IL-17A. On the other hand, experienced patients demonstrated a poor interaction between cytokines, chemokines, and cells with a strong correlation between IL-10, IL-6, CXCL-10, and CD8+ besides the interactions between IFN-γ and IL-4. Furthermore, naive and experienced patients seem to have a distinct soluble biomarker profile; therefore, a long-term follow-up is needed to evaluate patients treated with DAAs.
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21
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Kanevskiy L, Erokhina S, Kobyzeva P, Streltsova M, Sapozhnikov A, Kovalenko E. Dimorphism of HLA-E and its Disease Association. Int J Mol Sci 2019; 20:ijms20215496. [PMID: 31690066 PMCID: PMC6862560 DOI: 10.3390/ijms20215496] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 10/25/2019] [Accepted: 11/01/2019] [Indexed: 02/07/2023] Open
Abstract
HLA-E is a nonclassical member of the major histocompatibility complex class I gene locus. HLA-E protein shares a high level of homology with MHC Ia classical proteins: it has similar tertiary structure, associates with β2-microglobulin, and is able to present peptides to cytotoxic lymphocytes. The main function of HLA-E under normal conditions is to present peptides derived from the leader sequences of classical HLA class I proteins, thus serving for monitoring of expression of these molecules performed by cytotoxic lymphocytes. However, opposite to multiallelic classical MHC I genes, HLA-E in fact has only two alleles—HLA-E*01:01 and HLA-E*01:03—which differ by one nonsynonymous amino acid substitution at position 107, resulting in an arginine in HLA-E*01:01 (HLA-ER) and glycine in HLA-E*01:03 (HLA-EG). In contrast to HLA-ER,HLA-EG has higher affinity to peptide, higher surface expression, and higher thermal stability of the corresponding protein, and it is more ancient than HLA-ER, though both alleles are presented in human populations in nearly equal frequencies. In the current review, we aimed to uncover the reason of the expansion of the younger allele, HLA-ER, by analysis of associations of both HLA-E alleles with a number of diseases, including viral and bacterial infections, cancer, and autoimmune disorders.
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Affiliation(s)
- Leonid Kanevskiy
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
| | - Sofya Erokhina
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
| | - Polina Kobyzeva
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
| | - Maria Streltsova
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
| | - Alexander Sapozhnikov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
| | - Elena Kovalenko
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 16/10, Miklukho-Maklaya St., Moscow 117997, Russia.
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22
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Bertol BC, Dias FC, da Silva DM, Zambelli Ramalho LN, Donadi EA. Human Antigen Leucocyte (HLA)-G and HLA-E are differentially expressed in pancreatic disorders. Hum Immunol 2019; 80:948-954. [PMID: 31561913 DOI: 10.1016/j.humimm.2019.09.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 08/28/2019] [Accepted: 09/03/2019] [Indexed: 01/07/2023]
Abstract
BACKGROUND Little information is available regarding the expression of the immunomodulatory Human Leukocyte Antigen (HLA)-G and -E molecules in pancreatic disorders. AIM To analyze HLA-G and -E expression in specimens of alcoholic chronic pancreatitis (ACP), idiopathic chronic pancreatitis (ICP), type 1 (T1D) and type 2 diabetes (T2D) and in histologically normal pancreas (HNP). METHODS HLA-G and -E expression (ACP = 30, ICP = 10, T1D = 10, T2D = 30 and HNP = 20) was evaluated by immunohistochemistry in three different areas (acini, islets and inflammatory infiltrate). RESULTS Acini and islets from HNP specimens exhibited higher HLA-G and -E expression compared to corresponding areas from all other patient groups. In inflammatory infiltrate, HLA-G and -E expression was observed only among the pancreatic disorders. We observed higher HLA-G and -E expression in acini from T2D compared to ACP, as well as higher HLA-G expression compared to ICP. CONCLUSION The decreased expression of HLA-G and -E in islets and acini together with the expression of these molecules in the inflammatory infiltrating cells were shared features among chronic inflammatory and autoimmune pancreatic disorders evaluated in this study, possibly reflecting tissue damage.
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Affiliation(s)
- Bruna Cristina Bertol
- Postgraduate Program of Basic and Applied Immunology, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, ZIP Code: 14049-900 Ribeirão Preto, Brazil.
| | - Fabrício César Dias
- Department of Medicine, Division of Clinical Immunology, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, ZIP Code: 14049-900 Ribeirão Preto, Brazil.
| | - Deisy Mara da Silva
- Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, ZIP Code: 14049-900 Ribeirão Preto, Brazil.
| | - Leandra Náira Zambelli Ramalho
- Department of Pathology, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, ZIP Code: 14049-900 Ribeirão Preto, Brazil.
| | - Eduardo Antônio Donadi
- Postgraduate Program of Basic and Applied Immunology, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, ZIP Code: 14049-900 Ribeirão Preto, Brazil; Department of Medicine, Division of Clinical Immunology, Ribeirão Preto Medical School, University of São Paulo, 3900 Bandeirantes Avenue, ZIP Code: 14049-900 Ribeirão Preto, Brazil.
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Shiina T, Blancher A. The Cynomolgus Macaque MHC Polymorphism in Experimental Medicine. Cells 2019; 8:E978. [PMID: 31455025 PMCID: PMC6770713 DOI: 10.3390/cells8090978] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/20/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023] Open
Abstract
Among the non-human primates used in experimental medicine, cynomolgus macaques (Macaca fascicularis hereafter referred to as Mafa) are increasingly selected for the ease with which they are maintained and bred in captivity. Macaques belong to Old World monkeys and are phylogenetically much closer to humans than rodents, which are still the most frequently used animal model. Our understanding of the Mafa genome has progressed rapidly in recent years and has greatly benefited from the latest technical advances in molecular genetics. Cynomolgus macaques are widespread in Southeast Asia and numerous studies have shown a distinct genetic differentiation of continental and island populations. The major histocompatibility complex of cynomolgus macaque (Mafa MHC) is organized in the same way as that of human, but it differs from the latter by its high degree of classical class I gene duplication. Human polymorphic MHC regions play a pivotal role in allograft transplantation and have been associated with more than 100 diseases and/or phenotypes. The Mafa MHC polymorphism similarly plays a crucial role in experimental allografts of organs and stem cells. Experimental results show that the Mafa MHC class I and II regions influence the ability to mount an immune response against infectious pathogens and vaccines. MHC also affects cynomolgus macaque reproduction and impacts on numerous biological parameters. This review describes the Mafa MHC polymorphism and the methods currently used to characterize it. We discuss some of the major areas of experimental medicine where an effect induced by MHC polymorphism has been demonstrated.
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Affiliation(s)
- Takashi Shiina
- Department of Molecular Life Sciences, Division of Basic Medical Science and Molecular Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan
| | - Antoine Blancher
- Centre de Physiopathologie Toulouse-Purpan (CPTP), Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (Inserm), Université Paul Sabatier (UPS), Toulouse 31000, France.
- Laboratoire d'immunologie, CHU de Toulouse, Institut Fédératif de Biologie, hôpital Purpan, 330 Avenue de Grande Bretagne, TSA40031, 31059 Toulouse CEDEX 9, France.
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Toni Ho GG, Heinen F, Stieglitz F, Blasczyk R, Bade-Döding C. Dynamic Interaction between Immune Escape Mechanism and HLA-Ib Regulation. Immunogenetics 2019. [DOI: 10.5772/intechopen.80731] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Chigbu DI, Loonawat R, Sehgal M, Patel D, Jain P. Hepatitis C Virus Infection: Host⁻Virus Interaction and Mechanisms of Viral Persistence. Cells 2019; 8:cells8040376. [PMID: 31027278 PMCID: PMC6523734 DOI: 10.3390/cells8040376] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 03/25/2019] [Accepted: 04/17/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C (HCV) is a major cause of liver disease, in which a third of individuals with chronic HCV infections may develop liver cirrhosis. In a chronic HCV infection, host immune factors along with the actions of HCV proteins that promote viral persistence and dysregulation of the immune system have an impact on immunopathogenesis of HCV-induced hepatitis. The genome of HCV encodes a single polyprotein, which is translated and processed into structural and nonstructural proteins. These HCV proteins are the target of the innate and adaptive immune system of the host. Retinoic acid-inducible gene-I (RIG-I)-like receptors and Toll-like receptors are the main pattern recognition receptors that recognize HCV pathogen-associated molecular patterns. This interaction results in a downstream cascade that generates antiviral cytokines including interferons. The cytolysis of HCV-infected hepatocytes is mediated by perforin and granzyme B secreted by cytotoxic T lymphocyte (CTL) and natural killer (NK) cells, whereas noncytolytic HCV clearance is mediated by interferon gamma (IFN-γ) secreted by CTL and NK cells. A host-HCV interaction determines whether the acute phase of an HCV infection will undergo complete resolution or progress to the development of viral persistence with a consequential progression to chronic HCV infection. Furthermore, these host-HCV interactions could pose a challenge to developing an HCV vaccine. This review will focus on the role of the innate and adaptive immunity in HCV infection, the failure of the immune response to clear an HCV infection, and the factors that promote viral persistence.
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Affiliation(s)
- DeGaulle I Chigbu
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
- Pennsylvania College of Optometry at Salus University, Elkins Park, PA 19027, USA.
| | - Ronak Loonawat
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Mohit Sehgal
- Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
| | - Dip Patel
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Pooja Jain
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
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NKG2A is a NK cell exhaustion checkpoint for HCV persistence. Nat Commun 2019; 10:1507. [PMID: 30944315 PMCID: PMC6447531 DOI: 10.1038/s41467-019-09212-y] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 02/18/2019] [Indexed: 01/23/2023] Open
Abstract
Exhaustion of cytotoxic effector natural killer (NK) and CD8+ T cells have important functions in the establishment of persistent viral infections, but how exhaustion is induced during chronic hepatitis C virus (HCV) infection remains poorly defined. Here we show, using the humanized C/OTg mice permissive for persistent HCV infection, that NK and CD8+ T cells become sequentially exhausted shortly after their transient hepatic infiltration and activation in acute HCV infection. HCV infection upregulates Qa-1 expression in hepatocytes, which ligates NKG2A to induce NK cell exhaustion. Antibodies targeting NKG2A or Qa-1 prevents NK exhaustion and promotes NK-dependent HCV clearance. Moreover, reactivated NK cells provide sufficient IFN-γ that helps rejuvenate polyclonal HCV CD8+ T cell response and clearance of HCV. Our data thus show that NKG2A serves as a critical checkpoint for HCV-induced NK exhaustion, and that NKG2A blockade sequentially boosts interdependent NK and CD8+ T cell functions to prevent persistent HCV infection. Immune cells may become less responsive, or ‘exhausted’, upon chronic viral infection, but the underlying mechanism and crosstalk are still unclear. Here the authors show that, upon chronic hepatitis C virus (HCV) infection, natural killer cell exhaustion is induced by NKG2A signalling to instruct downstream exhaustion of CD8+ T cells and HCV persistence.
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Ravindranath MH, Filippone EJ, Devarajan A, Asgharzadeh S. Enhancing Natural Killer and CD8 + T Cell-Mediated Anticancer Cytotoxicity and Proliferation of CD8 + T Cells with HLA-E Monospecific Monoclonal Antibodies. Monoclon Antib Immunodiagn Immunother 2019; 38:38-59. [PMID: 31009335 PMCID: PMC6634170 DOI: 10.1089/mab.2018.0043] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Accepted: 01/13/2019] [Indexed: 12/16/2022] Open
Abstract
Cytotoxic NK/CD8+ T cells interact with MHC-I ligands on tumor cells through either activating or inhibiting receptors. One of the inhibitory receptors is CD94/NKG2A. The NK/CD8+ T cell cytotoxic capability is lost when tumor-associated human leukocyte antigen, HLA-E, binds the CD94/NKG2A receptor, resulting in tumor progression and reduced survival. Failure of cancer patients to respond to natural killer (NK) cell therapies could be due to HLA-E overexpression in tumor tissues. Preventing the inhibitory receptor-ligand interaction by either receptor- or ligand-specific monoclonal antibodies (mAbs) is an innovative passive immunotherapeutic strategy for cancer. Since receptors and ligands can be monomeric or homo- or heterodimeric proteins, the efficacy of mAbs may rely on their ability to distinguish monospecific (private) functional epitopes from nonfunctional common (public) epitopes. We developed monospecific anti-HLA-E mAbs (e.g., TFL-033) that recognize only HLA-E-specific epitopes, but not epitopes shared with other HLA class-I loci as occurs with currently available polyreactive anti-HLA-E mAbs. Interestingly the amino acid sequences in the α1 and α2 helices of HLA-E, critical for the recognition of the mAb TFL-033, are strikingly the same sequences recognized by the CD94/NKG2A inhibitory receptors on NK/CD8+ cells. Such monospecific mAbs can block the CD94/NKG2A interaction with HLA-E to restore NK cell and CD8+ anticancer cell cytotoxicity. Furthermore, the HLA-E monospecific mAbs significantly promoted the proliferation of the CD4-/CD8+ T cells. These monospecific mAbs are also invaluable for the specific demonstration of HLA-E on tumor biopsies, potentially indicating those tumors most likely to respond to such therapy. Thus, they can be used to enhance passive immunotherapy once phased preclinical studies and clinical trials are completed. On principle, we postulate that NK cell passive immunotherapy should capitalize on both of these features of monospecific HLA-E mAbs, that is, the specific determination HLA-E expression on a particular tumor and the enhancement of NK cell/CD8+ cytotoxicity if HLA-E positive.
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Affiliation(s)
| | - Edward J Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Asokan Devarajan
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Shahab Asgharzadeh
- Department of Pediatrics and Pathology, Children's Hospital, Keck School of Medicine, USC, Los Angeles, California
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Bastidas-Legarda LY, Khakoo SI. Conserved and variable natural killer cell receptors: diverse approaches to viral infections. Immunology 2019; 156:319-328. [PMID: 30570753 DOI: 10.1111/imm.13039] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 12/12/2018] [Indexed: 02/07/2023] Open
Abstract
Natural killer (NK) cells are lymphocytes of the innate immune system with essential roles during viral infections. NK cell functions are mediated through a repertoire of non-rearranging inhibitory and activating receptors that interact with major histocompatibility complex (MHC)-peptide complexes on the surface of infected cells. Recent work studying the conserved CD94-NKG2A and variable killer cell immunoglobulin-like receptor-MHC systems suggest that these two receptor families may have subtly different properties in terms of interactions with MHC class I bound peptides, and in recognition of down-regulation of MHC class I. In this review, we discuss how these properties generate diversity in the NK cell response to viruses.
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Affiliation(s)
- Leidy Y Bastidas-Legarda
- Faculty of Medicine, Clinical and Experimental Sciences, Southampton General Hospital, University of Southampton, Southampton, UK
| | - Salim I Khakoo
- Faculty of Medicine, Clinical and Experimental Sciences, Southampton General Hospital, University of Southampton, Southampton, UK
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Nafady A, Nafady-Hego H, Abdelwahab NM, Eltellawy RHN, Abu Faddan NH. Peripheral lymphocytes analyses in children with chronic hepatitis C virus infection. Eur J Clin Invest 2018; 48:e13004. [PMID: 30022474 DOI: 10.1111/eci.13004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 05/24/2018] [Accepted: 07/16/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV)-specific immune response is believed to play a crucial role in viral clearance. There is, nevertheless, no reliable parameter to monitor this immune response or predict chronic HCV infection development. METHOD An observational case-control study was performed to identify such parameters, peripheral blood mononuclear cells from 57 children with chronic HCV were systemically phenotyped, and the serum level of Interferon gamma and interleukin (IL) -17 was measured. The data were compared with 37 age-matched healthy volunteers (controls). RESULTS Children with chronic HCV infection had a lower frequency of natural killer cells (NK) cells, CD56Dim NK cells and expansion of CD56Bright NK cells compared with controls (P = 0.001, P < 0.0001 and P < 0.0001 respectively). Increased CD56Dim NK cells were negatively correlated with the higher viral load, R2 = 0.29, P = 0.05, while, increased NK T cells were positively correlated with high viral load, R2 = 0.17, P = 0.011. T helper cells, naive T cells, CD127 negative T cells, and HLA-DR-positive T cells significantly increased in patients than in controls. The frequency of CD4+CD25high+ T regulatory (Treg) cells increased in HCV-infected patients, compared with those in control, and FOXP3 was upregulated within them. Treg cells' increase was positively correlated with high viral load, R2 = 0.45, P = 0.004. The level of IL-17 was higher in HCV patients than that in control, P < 0.0001. CONCLUSION Although the contribution of those markers to the chronic HCV establishment in children remains elusive, the results may provide important clues for reliable indicators of HCV infection.
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Affiliation(s)
- Asmaa Nafady
- Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Department of Clinical and Chemical Pathology, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Hanaa Nafady-Hego
- Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nadia M Abdelwahab
- Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Radwa H N Eltellawy
- Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nagla H Abu Faddan
- Department of Pediatrics, children hospital, Faculty of Medicine, Assiut University, Assiut, Egypt
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Hannoun Z, Lin Z, Brackenridge S, Kuse N, Akahoshi T, Borthwick N, McMichael A, Murakoshi H, Takiguchi M, Hanke T. Identification of novel HIV-1-derived HLA-E-binding peptides. Immunol Lett 2018; 202:65-72. [PMID: 30172717 PMCID: PMC6291738 DOI: 10.1016/j.imlet.2018.08.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 08/07/2018] [Accepted: 08/23/2018] [Indexed: 01/13/2023]
Abstract
Non-classical class Ib MHC-E molecule is becoming an increasingly interesting component of the immune response. It is involved in both the adaptive and innate immune responses to several chronic infections including HIV-1 and, under very specific circumstances, likely mediated a unique vaccine protection of rhesus macaques against pathogenic SIV challenge. Despite being recently in the spotlight for HIV-1 vaccine development, to date there is only one reported human leukocyte antigen (HLA)-E-binding peptide derived from HIV-1. In an effort to help start understanding the possible functions of HLA-E in HIV-1 infection, we determined novel HLA-E binding peptides derived from HIV-1 Gag, Pol and Vif proteins. These peptides were identified in three independent assays, all quantifying cell-surface stabilization of HLA-E*01:01 or HLA-E*01:03 molecules upon peptide binding, which was detected by HLA-E-specific monoclonal antibody and flow cytometry. Thus, following initial screen of over 400 HIV-1-derived 15-mer peptides, 4 novel 9-mer peptides PM9, RL9, RV9 and TP9 derived from 15-mer binders specifically stabilized surface expression of HLA-E*01:03 on the cell surface in two separate assays and 5 other binding candidates EI9, MD9, NR9, QF9 and YG9 gave a binding signal in only one of the two assays, but not both. Overall, we have expanded the current knowledge of HIV-1-derived target peptides stabilizing HLA-E cell-surface expression from 1 to 5, thus broadening inroads for future studies. This is a small, but significant contribution towards studying the fine mechanisms behind HLA-E actions and their possible use in development of a new kind of vaccines.
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Affiliation(s)
- Zara Hannoun
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Zhansong Lin
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | - Simon Brackenridge
- NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Nozomi Kuse
- Center for AIDS Research, Kumamoto University, Kumamoto, Japan
| | | | - Nicola Borthwick
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Andrew McMichael
- NDM Research Building, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | | | | | - Tomáš Hanke
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom; International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
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Li Y, Zeng Y, Zeng G, Li J, Zhang X, Cai Q, Chen Y, Lin CS. The effects of direct-acting antiviral agents on the frequency of myeloid-derived suppressor cells and natural killer cells in patients with chronic hepatitis C. J Med Virol 2018; 91:278-286. [PMID: 30171691 DOI: 10.1002/jmv.25302] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 07/27/2018] [Indexed: 12/26/2022]
Abstract
Currently, hepatitis C antiviral therapy is entering a new era with the use of direct-acting antiviral (DAA) agents. However, the precise immunological influences of DAA therapy in patients with chronic hepatitis C (CHC) are insufficiently understood. This study aimed to investigate the effects of DAA therapy on the frequency of myeloid-derived suppressor cells (MDSCs), T lymphocytes, and natural killer (NK) cells in patients with CHC. Thirty-two treatment-naive CHC patients were treated with DAA therapy, and the frequency of immune cells was analyzed by flow cytometry at various time points during and after therapy. Sixteen healthy donors were recruited for comparison. DAA therapy decreased the frequency of MDSCs and monocytic MDSCs in patients with CHC to a normal level. DAA therapy also increased the CD8+ T and NK cell levels in patients with CHC. In addition, activation (NKp30 and NKp46) and inhibitory (NKG2A) receptors on NK cells were downregulated to yield an NK cell phenotype resembling that observed in the healthy controls. This study provides insight into the normalization of immune cell levels under DAA therapy and indicates that restoration of the immune system in patients with CHC strongly supports long-term curative hepatitis C virus eradication.
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Affiliation(s)
- Yiting Li
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yingfu Zeng
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Guofen Zeng
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jianguo Li
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Xiaohong Zhang
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Qingxian Cai
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Youming Chen
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Chao-Shuang Lin
- Department of Infectious Diseases, Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
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Lymphocytes Negatively Regulate NK Cell Activity via Qa-1b following Viral Infection. Cell Rep 2018; 21:2528-2540. [PMID: 29186689 DOI: 10.1016/j.celrep.2017.11.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 10/02/2017] [Accepted: 10/30/2017] [Indexed: 01/26/2023] Open
Abstract
NK cells can reduce anti-viral T cell immunity during chronic viral infections, including infection with the lymphocytic choriomeningitis virus (LCMV). However, regulating factors that maintain the equilibrium between productive T cell and NK cell immunity are poorly understood. Here, we show that a large viral load resulted in inhibition of NK cell activation, which correlated with increased expression of Qa-1b, a ligand for inhibitory NK cell receptors. Qa-1b was predominantly upregulated on B cells following LCMV infection, and this upregulation was dependent on type I interferons. Absence of Qa-1b resulted in increased NK cell-mediated regulation of anti-viral T cells following viral infection. Consequently, anti-viral T cell immunity was reduced in Qa-1b- and NKG2A-deficient mice, resulting in increased viral replication and immunopathology. NK cell depletion restored anti-viral immunity and virus control in the absence of Qa-1b. Taken together, our findings indicate that lymphocytes limit NK cell activity during viral infection in order to promote anti-viral T cell immunity.
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Araújo RC, Dias FC, Bertol BC, Silva DM, Almeida PH, Teixeira AC, Souza FF, Villanova MG, Ramalho LNZ, Donadi EA, Martinelli ALC. Liver HLA-E Expression Is Associated with Severity of Liver Disease in Chronic Hepatitis C. J Immunol Res 2018; 2018:2563563. [PMID: 29951556 PMCID: PMC5987287 DOI: 10.1155/2018/2563563] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 04/16/2018] [Accepted: 04/24/2018] [Indexed: 12/31/2022] Open
Abstract
Hepatitis C virus (HCV) can escape from innate and adaptive immunity, making the immune response ineffective. Human leukocyte antigen E (HLA-E) might regulate the antiviral function of immune response and contribute to the persistence of HCV and the severity of liver disease. This study aimed to evaluate the expression of HLA-E in the liver and its association with the severity of liver disease in HCV patients. We performed a retrospective analysis of liver biopsies from 125 HCV patients and from 20 control subjects without liver disease. Liver biopsies were reviewed and classified according to severity of fibrosis and inflammatory activity. The pathologist assessed the magnitude of HLA-E expression in a semiquantitative way, attributing scores from 0 to 3. Immunohistochemistry showed positive for HLA-E in hepatocyte and Kupffer cells. The rate of HLA-E positivity in hepatocytes and Kupffer cells was significantly higher in HCV patients compared to controls. The liver samples classified as severe fibrosis and necroinflammatory activity presented greater expression of HLA-E on Kupffer cells and hepatocytes, with a significant linear association. It indicates that HLA-E expression may have an immunomodulatory effect and a possible role in the severity of liver disease in chronic hepatitis C.
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Affiliation(s)
- Roberta C. Araújo
- Gastroenterology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, SP, Brazil
| | - Fabricio C. Dias
- Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, SP, Brazil
| | - Bruna C. Bertol
- Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, SP, Brazil
| | - Deisy M. Silva
- Pathology Department, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, SP, Brazil
| | - Patrícia H. Almeida
- Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, SP, Brazil
| | - Andreza C. Teixeira
- Gastroenterology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, SP, Brazil
| | - Fernanda F. Souza
- Gastroenterology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, SP, Brazil
| | - Marcia G. Villanova
- Gastroenterology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, SP, Brazil
| | - Leandra N. Z. Ramalho
- Pathology Department, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, SP, Brazil
| | - Eduardo A. Donadi
- Immunology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, SP, Brazil
| | - Ana L. C. Martinelli
- Gastroenterology Division, Ribeirão Preto Medical School, University of São Paulo, 14048-900 Ribeirão Preto, SP, Brazil
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Doorduijn EM, Sluijter M, Querido BJ, Seidel UJE, Oliveira CC, van der Burg SH, van Hall T. T Cells Engaging the Conserved MHC Class Ib Molecule Qa-1 b with TAP-Independent Peptides Are Semi-Invariant Lymphocytes. Front Immunol 2018; 9:60. [PMID: 29422902 PMCID: PMC5788890 DOI: 10.3389/fimmu.2018.00060] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 01/10/2018] [Indexed: 12/12/2022] Open
Abstract
The HLA-E homolog in the mouse (Qa-1b) is a conserved MHC class Ib molecule presenting monomorphic peptides to germline-encoded natural killer receptor CD94/NKG2A. Previously, we demonstrated the replacement of this canonical peptide by a diverse peptidome upon deficiency of the TAP peptide transporter. Analysis of this Qa-1b-restricted T cell repertoire against these non-mutated neoantigens revealed characteristics of conventional hypervariable CD8+ T cells, but also of invariant T cell receptor (TCR)αβ T cells. A shared TCR Vα chain was used by this subset in combination with a variety of Vβ chains. The TCRs target peptide ligands that are conserved between mouse and man, like the identified peptide derived from the transcriptional cofactor Med15. The thymus selection was studied in a TCR-transgenic mouse and emerging naïve CD8+ T cells displayed a slightly activated phenotype, as witnessed by higher CD122 and Ly6C expression. Moreover, the Qa-1b protein was dispensable for thymus selection. Importantly, no self-reactivity was observed as reported for other MHC class Ib-restricted subsets. Naïve Qa-1b restricted T cells expanded, contracted, and formed memory cells in vivo upon peptide vaccination in a similar manner as conventional CD8+ T cells. Based on these data, the Qa-1b restricted T cell subset might be positioned closest to conventional CD8+ T cells of all MHC class Ib populations.
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Affiliation(s)
- Elien M Doorduijn
- Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Marjolein Sluijter
- Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Bianca J Querido
- Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Ursula J E Seidel
- Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Claudia C Oliveira
- Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Sjoerd H van der Burg
- Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, Netherlands
| | - Thorbald van Hall
- Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, Netherlands
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Wu HL, Wiseman RW, Hughes CM, Webb GM, Abdulhaqq SA, Bimber BN, Hammond KB, Reed JS, Gao L, Burwitz BJ, Greene JM, Ferrer F, Legasse AW, Axthelm MK, Park BS, Brackenridge S, Maness NJ, McMichael AJ, Picker LJ, O'Connor DH, Hansen SG, Sacha JB. The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 200:49-60. [PMID: 29150562 PMCID: PMC5736429 DOI: 10.4049/jimmunol.1700841] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 10/23/2017] [Indexed: 11/19/2022]
Abstract
MHC-E is a highly conserved nonclassical MHC class Ib molecule that predominantly binds and presents MHC class Ia leader sequence-derived peptides for NK cell regulation. However, MHC-E also binds pathogen-derived peptide Ags for presentation to CD8+ T cells. Given this role in adaptive immunity and its highly monomorphic nature in the human population, HLA-E is an attractive target for novel vaccine and immunotherapeutic modalities. Development of HLA-E-targeted therapies will require a physiologically relevant animal model that recapitulates HLA-E-restricted T cell biology. In this study, we investigated MHC-E immunobiology in two common nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM). Compared to humans and MCM, RM expressed a greater number of MHC-E alleles at both the population and individual level. Despite this difference, human, RM, and MCM MHC-E molecules were expressed at similar levels across immune cell subsets, equivalently upregulated by viral pathogens, and bound and presented identical peptides to CD8+ T cells. Indeed, SIV-specific, Mamu-E-restricted CD8+ T cells from RM recognized antigenic peptides presented by all MHC-E molecules tested, including cross-species recognition of human and MCM SIV-infected CD4+ T cells. Thus, MHC-E is functionally conserved among humans, RM, and MCM, and both RM and MCM represent physiologically relevant animal models of HLA-E-restricted T cell immunobiology.
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Affiliation(s)
- Helen L Wu
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
| | - Roger W Wiseman
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53706
| | - Colette M Hughes
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
| | - Gabriela M Webb
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
| | - Shaheed A Abdulhaqq
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
| | - Benjamin N Bimber
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
| | - Katherine B Hammond
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
| | - Jason S Reed
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
| | - Lina Gao
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
- Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239
| | - Benjamin J Burwitz
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
| | - Justin M Greene
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
| | - Fidel Ferrer
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
| | - Alfred W Legasse
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
| | - Michael K Axthelm
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
| | - Byung S Park
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
- School of Public Health, Oregon Health and Science University, Portland, OR 97239
| | - Simon Brackenridge
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX1 2JD, United Kingdom
| | - Nicholas J Maness
- Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433
- Department of Microbiology and Immunology, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70118; and
| | - Andrew J McMichael
- Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX1 2JD, United Kingdom
| | - Louis J Picker
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
| | - David H O'Connor
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53706
- Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715
| | - Scott G Hansen
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006
| | - Jonah B Sacha
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006;
- Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006
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36
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Hölzemer A, Garcia-Beltran WF, Altfeld M. Natural Killer Cell Interactions with Classical and Non-Classical Human Leukocyte Antigen Class I in HIV-1 Infection. Front Immunol 2017; 8:1496. [PMID: 29184550 PMCID: PMC5694438 DOI: 10.3389/fimmu.2017.01496] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 10/24/2017] [Indexed: 11/23/2022] Open
Abstract
Natural killer (NK) cells are effector lymphocytes of the innate immune system that are able to mount a multifaceted antiviral response within hours following infection. This is achieved through an array of cell surface receptors surveilling host cells for alterations in human leukocyte antigen class I (HLA-I) expression and other ligands as signs of viral infection, malignant transformation, and cellular stress. This interaction between HLA-I ligands and NK-cell receptor is not only important for recognition of diseased cells but also mediates tuning of NK-cell-effector functions. HIV-1 alters the expression of HLA-I ligands on infected cells, rendering them susceptible to NK cell-mediated killing. However, over the past years, various HIV-1 evasion strategies have been discovered to target NK-cell-receptor ligands and allow the virus to escape from NK cell-mediated immunity. While studies have been mainly focusing on the role of polymorphic HLA-A, -B, and -C molecules, less is known about how HIV-1 affects the more conserved, non-classical HLA-I molecules HLA-E, -G, and -F. In this review, we will focus on the recent progress in understanding the role of non-classical HLA-I ligands in NK cell-mediated recognition of HIV-1-infected cells.
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Affiliation(s)
- Angelique Hölzemer
- First Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
| | | | - Marcus Altfeld
- German Center for Infection Research (DZIF), Partner site Hamburg-Lübeck-Borstel-Riems, Hamburg, Germany
- Institute for Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Fernández-Ponce C, Dominguez-Villar M, Muñoz-Miranda JP, Arbulo-Echevarria MM, Litrán R, Aguado E, García-Cozar F. Immune modulation by the hepatitis C virus core protein. J Viral Hepat 2017; 24:350-356. [PMID: 28092420 DOI: 10.1111/jvh.12675] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 12/22/2016] [Indexed: 12/14/2022]
Abstract
Hepatitis C virus (HCV) infection is currently the most important cause of chronic viral hepatitis in the world and one of the most frequent indications for liver transplantation. HCV uses different strategies to evade the innate and adaptive immune response, and this evasion plays a key role in determining viral persistence. Several HCV viral proteins have been described as immune modulators. In this review, we will focus on the effect of HCV nucleocapsid core protein in the function of immune cells and its correlation with the findings observed in HCV chronically infected patients. Effects on immune cell function related to both extracellular and intracellular HCV core localization will be considered. This review provides an updated perspective on the mechanisms involved in HCV evasion related to one single HCV protein, which could become a key tool in the development of new antiviral strategies able to control and/or eradicate HCV infection.
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Affiliation(s)
- C Fernández-Ponce
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain
| | - M Dominguez-Villar
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain.,Department of Neurology, Human Translational Immunology Program, Yale School of Medicine, 300 George St. 353D, New Haven, 06520, CT
| | - J P Muñoz-Miranda
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain
| | - M M Arbulo-Echevarria
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain
| | - R Litrán
- Department of Condensed Matter Physics, University of Cádiz, Puerto Real, Cádiz, Spain
| | - E Aguado
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain
| | - F García-Cozar
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Institute of Biomedical Research Cádiz (INIBICA), Cadiz, Spain
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Yang CM, Yoon JC, Park JH, Lee JM. Hepatitis C virus impairs natural killer cell activity via viral serine protease NS3. PLoS One 2017; 12:e0175793. [PMID: 28410411 PMCID: PMC5391949 DOI: 10.1371/journal.pone.0175793] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Accepted: 03/31/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatitis C virus (HCV) infection is characterized by a high frequency of chronic cases owing to the impairment of innate and adaptive immune responses. The modulation of natural killer (NK) cell functions by HCV leads to an impaired innate immune response. However, the underling mechanisms and roles of HCV proteins in this immune evasion are controversial, especially in the early phase of HCV infection. To investigate the role of HCV nonstructural proteins especially NS3 in the impairment of NK functions, NK cells were isolated from the PBMCs by negative selection. To assess the direct cytotoxicity and IFN-γ production capability of NK cells, co-cultured with uninfected, HCV-infected, HCV-NS3 DNA-transfected Huh-7.5, or HCV-NS replicon cells. To determine the effect of an NS3 serine protease inhibitor, HCV-infected Huh-7.5 cells were treated with BILN-2061. Then, NK cells were harvested and further co-cultured with K-562 target cells. NK cell functions were analyzed by flow cytometry and enzyme-linked immunosorbent assay. When co-cultured with HCV-infected Huh-7.5 cells, the natural cytotoxicity and IFN-γ production capability of NK cells were significantly reduced. NK cell functions were inhibited to similar levels upon co-culture with HCV-NS replicon cells, NS3-transfected cells, and HCV-infected Huh-7.5 cells. These reductions were restored by BILN-2061-treatment. Furthermore, BILN-2061-treatment significantly increased degranulation against K-562 target cells and IFN-γ productivity in NK cells. Consistent with these findings, the expression levels of activating NK cell receptors, such as NKp46 and NKp30, were also increased. In HCV-infected cells, the serine protease NS3 may play a role in the abrogation of NK cell functions in the early phase of infection through downregulation of NKp46 and NKp30 receptors on NK cells. Together, these results suggest that NS3 represents a novel drug target for the treatment of HCV infections.
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Affiliation(s)
- Chang Mo Yang
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases and Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Joo Chun Yoon
- Department of Microbiology and Tissue Injury Defense Research Center, Ewha Womans University School of Medicine, Seoul, Republic of Korea
| | - Jeon Han Park
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases and Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae Myun Lee
- Department of Microbiology and Immunology, Institute for Immunology and Immunological Diseases and Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
- * E-mail:
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39
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Aquino-López A, Senyukov VV, Vlasic Z, Kleinerman ES, Lee DA. Interferon Gamma Induces Changes in Natural Killer (NK) Cell Ligand Expression and Alters NK Cell-Mediated Lysis of Pediatric Cancer Cell Lines. Front Immunol 2017; 8:391. [PMID: 28428785 PMCID: PMC5382194 DOI: 10.3389/fimmu.2017.00391] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Accepted: 03/20/2017] [Indexed: 12/12/2022] Open
Abstract
Natural killer (NK) cells have therapeutic potential for cancer due to their capacity for targeting tumor cells without prior sensitization. Our laboratory has developed an NK cell expansion protocol that generates large quantities of NK cells for therapeutic infusion that secret 20 times the amount of interferon gamma (IFNγ) than resting NK cells. IFNγ can upregulate major histocompatibility complex (MHC)-class I, an inhibitory ligand for NK cells, but can also upregulate intercellular adhesion molecule 1 (ICAM-1) which promotes NK:target cell interaction for an efficient lysis. Due to the opposing effects reported for IFNγ on tumor sensitivity to NK cells, we evaluated a panel 22 tumor cell lines from the pediatric preclinical testing program corresponding to different tumor types. We determined the impact of IFNγ on their expression of NK cell activating and inhibitory ligands, death receptors, and adhesion molecules using mass cytometry. We also evaluated the effect of IFNγ on their sensitivity to NK cell-mediated lysis. Our results show upregulation of PD-L1, ICAM-1, MHC-class I, HLA-DR, CD95/FasR, and CD270/HVEM after IFNγ treatment, this upregulation is variable across different tumor types. We also observed a variable impact of IFNγ in NK cell-mediated lysis. For six of the cancer cell lines IFNγ resulted in increased resistance to NK cells, while for three of them it resulted in increased sensitivity. Modeling of the data suggests that the effect of IFNγ on NK cell-mediated tumor lysis is mostly dependent on changes in MHC-class I and ICAM-1 expression. For three of the cell lines with increased resistance, we observed higher upregulation of MHC-class I than ICAM-1. For the cell lines with increased sensitivity after IFNγ treatment, we observed upregulation of ICAM-1 exceeding MHC-class I upregulation. ICAM-1 upregulation resulted in increased conjugate formation between the NK cells and tumor cells, which can contribute to the increased sensitivity observed. However, the effects of MHC-class I and ICAM-1 are not readily predictable. Due to the high IFNγ secretion of NK cell infusion products, a better understanding of the NK ligands on tumor cells and how they are affected by IFNγ is essential to optimize NK cell immunotherapy.
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Affiliation(s)
- Arianexys Aquino-López
- Department of Pediatric Research, The University of Texas M.D. Anderson Cancer Center, Graduate School of Biomedical Sciences, Houston, TX, USA.,School of Medicine, University of Puerto Rico, San Juan, Puerto Rico
| | - Vladimir V Senyukov
- Department of Pediatric Research, The University of Texas M.D. Anderson Cancer Center, Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Zlatko Vlasic
- Department of Pediatric Research, The University of Texas M.D. Anderson Cancer Center, Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Eugenie S Kleinerman
- Department of Pediatric Research, The University of Texas M.D. Anderson Cancer Center, Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Dean A Lee
- Center for Childhood Cancer and Blood Disorders, The Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
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López-Botet M, Vilches C, Redondo-Pachón D, Muntasell A, Pupuleku A, Yélamos J, Pascual J, Crespo M. Dual Role of Natural Killer Cells on Graft Rejection and Control of Cytomegalovirus Infection in Renal Transplantation. Front Immunol 2017; 8:166. [PMID: 28261220 PMCID: PMC5311043 DOI: 10.3389/fimmu.2017.00166] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 02/02/2017] [Indexed: 12/20/2022] Open
Abstract
Allograft rejection constitutes a major complication of solid organ transplantation requiring prophylactic/therapeutic immunosuppression, which increases susceptibility of patients to infections and cancer. Beyond the pivotal role of alloantigen-specific T cells and antibodies in the pathogenesis of rejection, natural killer (NK) cells may display alloreactive potential in case of mismatch between recipient inhibitory killer-cell immunoglobulin-like receptors (KIRs) and graft HLA class I molecules. Several studies have addressed the impact of this variable in kidney transplant with conflicting conclusions; yet, increasing evidence supports that alloantibody-mediated NK cell activation via FcγRIIIA (CD16) contributes to rejection. On the other hand, human cytomegalovirus (HCMV) infection constitutes a risk factor directly associated with the rate of graft loss and reduced host survival. The levels of HCMV-specific CD8+ T cells have been reported to predict the risk of posttransplant infection, and KIR-B haplotypes containing activating KIR genes have been related with protection. HCMV infection promotes to a variable extent an adaptive differentiation and expansion of a subset of mature NK cells, which display the CD94/NKG2C-activating receptor. Evidence supporting that adaptive NKG2C+ NK cells may contribute to control the viral infection in kidney transplant recipients has been recently obtained. The dual role of NK cells in the interrelation of HCMV infection with rejection deserves attention. Further phenotypic, functional, and genetic analyses of NK cells may provide additional insights on the pathogenesis of solid organ transplant complications, leading to the development of biomarkers with potential clinical value.
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Affiliation(s)
- Miguel López-Botet
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Department of Immunology, Hospital del Mar, Barcelona, Spain; Univ. Pompeu Fabra, Barcelona, Spain
| | - Carlos Vilches
- Immunogenetics-Histocompatibility, Instituto de Investigación Sanitaria Puerta de Hierro , Majadahonda , Spain
| | - Dolores Redondo-Pachón
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Department of Nephrology, Hospital del Mar, Barcelona, Spain
| | - Aura Muntasell
- Hospital del Mar Medical Research Institute (IMIM) , Barcelona , Spain
| | | | - José Yélamos
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Department of Immunology, Hospital del Mar, Barcelona, Spain
| | - Julio Pascual
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Department of Nephrology, Hospital del Mar, Barcelona, Spain
| | - Marta Crespo
- Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain; Department of Nephrology, Hospital del Mar, Barcelona, Spain
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Gavlovsky PJ, Tonnerre P, Guitton C, Charreau B. Expression of MHC class I-related molecules MICA, HLA-E and EPCR shape endothelial cells with unique functions in innate and adaptive immunity. Hum Immunol 2016; 77:1084-1091. [PMID: 26916837 DOI: 10.1016/j.humimm.2016.02.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Revised: 02/03/2016] [Accepted: 02/18/2016] [Indexed: 10/22/2022]
Abstract
Endothelial cells (ECs) located at the interface of blood and tissues display regulatory activities toward coagulation, inflammation and vascular homeostasis. By expressing MHC class I and II antigens, ECs also contribute to immune responses. In transplantation, graft ECs are both trigger and target of alloimmune responses. ECs express a set of MHC class I-like or structural related molecules such as HLA-E, MHC class I related chain A (MICA) and the endothelial protein C receptor (EPCR) that provide multiple and unique functions to ECs. HLA-E is a low polymorphic ligand for the CD94/NKG2A/C receptors, and triggers HLA-E-restricted CD8+αβT cell responses against viral and bacterial peptides. MICA is a highly polymorphic ligand for NKG2D activating NK and costimulating CD8+T cells and a ligand for tissue-resident Vδ1 γδ T subsets. More intriguing is the role of EPCR, a key regulator of coagulation, as a ligand for a circulating subset of Vδ2- γδ T cells. Coexpression of this set of MHC class I-related molecules that allow ECs to activate a subtle array of immune responses upon stress and infection may also influence transplant outcome. Here, the respective structure, expression, and functions of HLA-E, MICA and EPCR as well as the impact of their polymorphism are reviewed.
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Affiliation(s)
- Pierre-Jean Gavlovsky
- INSERM, UMR1064, LabEx Transplantex, Nantes F44000, France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, ITUN, Nantes F44000, France; LUNAM Université de Nantes, Faculté de Médecine, Nantes F44000, France; IHU-CESTI, Nantes F44000, France
| | - Pierre Tonnerre
- INSERM, UMR1064, LabEx Transplantex, Nantes F44000, France; LUNAM Université de Nantes, Faculté de Médecine, Nantes F44000, France
| | - Christophe Guitton
- INSERM, UMR1064, LabEx Transplantex, Nantes F44000, France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, ITUN, Nantes F44000, France; LUNAM Université de Nantes, Faculté de Médecine, Nantes F44000, France
| | - Béatrice Charreau
- INSERM, UMR1064, LabEx Transplantex, Nantes F44000, France; CHU Nantes, Institut de Transplantation et de Recherche en Transplantation-Urologie-Néphrologie, ITUN, Nantes F44000, France; LUNAM Université de Nantes, Faculté de Médecine, Nantes F44000, France.
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42
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Joosten SA, Sullivan LC, Ottenhoff THM. Characteristics of HLA-E Restricted T-Cell Responses and Their Role in Infectious Diseases. J Immunol Res 2016; 2016:2695396. [PMID: 27699181 PMCID: PMC5028793 DOI: 10.1155/2016/2695396] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 06/28/2016] [Accepted: 07/10/2016] [Indexed: 12/31/2022] Open
Abstract
Human HLA-E can, in addition to self-antigens, also present pathogen-derived sequences, which elicit specific T-cell responses. T-cells recognize their antigen presented by HLA-E highly specifically and have unique functional and phenotypical properties. Pathogen specific HLA-E restricted CD8+ T-cells are an interesting new player in the field of immunology. Future work should address their exact roles and relative contributions in the immune response against infectious diseases.
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Affiliation(s)
- Simone A. Joosten
- Department of Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, Netherlands
| | - Lucy C. Sullivan
- Department of Microbiology and Immunology, The University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3010, Australia
| | - Tom H. M. Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, Netherlands
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44
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Anderson CK, Brossay L. The role of MHC class Ib-restricted T cells during infection. Immunogenetics 2016; 68:677-91. [PMID: 27368413 DOI: 10.1007/s00251-016-0932-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 05/22/2016] [Indexed: 01/02/2023]
Abstract
Even though major histocompatibility complex (MHC) class Ia and many Ib molecules have similarities in structure, MHC class Ib molecules tend to have more specialized functions, which include the presentation of non-peptidic antigens to non-classical T cells. Likewise, non-classical T cells also have unique characteristics, including an innate-like phenotype in naïve animals and rapid effector functions. In this review, we discuss the role of MAIT and NKT cells during infection but also the contribution of less studied MHC class Ib-restricted T cells such as Qa-1-, Qa-2-, and M3-restricted T cells. We focus on describing the types of antigens presented to non-classical T cells, their response and cytokine profile following infection, as well as the overall impact of these T cells to the immune system.
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Affiliation(s)
- Courtney K Anderson
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Box G-B618, Providence, RI, 02912, USA
| | - Laurent Brossay
- Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Box G-B618, Providence, RI, 02912, USA.
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Prasetyo AA, Dharmawan R, Raharjo I, Hudiyono. Human Leukocyte Antigen-E Alleles are Associated with Hepatitis C Virus, Torque Teno Virus, and Toxoplasma Co-infections but are not Associated with Hepatitis B Virus, Hepatitis D Virus, and GB Virus C Co-infections in Human Immunodeficiency Virus Patients. J Glob Infect Dis 2016; 8:75-81. [PMID: 27293362 PMCID: PMC4879794 DOI: 10.4103/0974-777x.182121] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Context: Data regarding the distribution of Human Leukocyte Antigen (HLA)-E alleles and their association with blood-borne pathogen infections/co-infections are limited for many populations, including Indonesia. Aims: The aim of this study was to analyze the association between HLA-E allelic variants and infection with blood-borne pathogens such as hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), torque teno virus (TTV), GB virus C (GBV-C), and Toxoplasma gondii (T. gondii) in Indonesian Javanese human immunodeficiency virus (HIV) patients. Settings and Design: A total of 320 anti-HIV-positive blood samples were analyzed for HBV, HCV, HDV, TTV, GBV-C, and T. gondii infection status and its association with HLA-E allelic variants. Materials and Methods: Nucleic acid was extracted from plasma samples and used for the molecular detection of HBV DNA, HCV RNA, HDV RNA, TTV DNA, and GBV-C RNA, whereas hepatitis B surface antigen, anti-HCV, immunoglobulin M and G (IgM and IgG) anti-T. gondii were detected through serological testing. The blood samples were genotyped for HLA-E loci using a sequence-specific primer-polymerase chain reaction. Statistical Analysis Used: Either the Chi-square or Fisher's exact test was performed to analyze the frequency of HLA-E alleles and blood-borne pathogen infections in the population. Odds ratios (ORs) were calculated to measure the association between the antibodies found and the participants’ possible risk behaviors. A logistic regression analysis was used to assess the associations. Results: HLA-E*101/0101 was associated with HCV/TTV co-infection (adjusted OR [aOR]: 3.5; 95% confidence interval [CI]: 1.156-10.734; P = 0.027) and IgM/IgG anti-Toxo positivity (aOR: 27.0; 95% CI: 3.626-200.472; P = 0.001). HLA-E*103/0103 was associated with TTV co-infection (aOR: 2.7; 95% CI: 1.509-4.796; P = 0.001). Conclusions: HLA-E alleles in Indonesian Javanese HIV patients were found to be associated with HCV, TTV, and toxoplasma co-infections.
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Affiliation(s)
- Afiono Agung Prasetyo
- A-IGIC (A-Infection, Genomic, Immunology & Cancer) Research Group, Sutami 36A, Surakarta, Indonesia; Department of Microbiology, Faculty of Medicine, Sutami 36A, Surakarta, Indonesia; Center of Biotechnology and Biodiversity Research and Development, Sebelas Maret University, Jl. Ir. Sutami 36A, Surakarta, Indonesia
| | - Ruben Dharmawan
- A-IGIC (A-Infection, Genomic, Immunology & Cancer) Research Group, Sutami 36A, Surakarta, Indonesia; Department of Parasitology, Faculty of Medicine, Surakarta, Indonesia
| | - Irvan Raharjo
- A-IGIC (A-Infection, Genomic, Immunology & Cancer) Research Group, Sutami 36A, Surakarta, Indonesia
| | - Hudiyono
- A-IGIC (A-Infection, Genomic, Immunology & Cancer) Research Group, Sutami 36A, Surakarta, Indonesia; Department of Microbiology, Faculty of Medicine, Sutami 36A, Surakarta, Indonesia; Center of Biotechnology and Biodiversity Research and Development, Sebelas Maret University, Jl. Ir. Sutami 36A, Surakarta, Indonesia
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Szereday L, Meggyes M, Halasz M, Szekeres-Bartho J, Par A, Par G. Immunological changes in different patient populations with chronic hepatitis C virus infection. World J Gastroenterol 2016; 22:4848-4859. [PMID: 27239111 PMCID: PMC4873877 DOI: 10.3748/wjg.v22.i20.4848] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 03/05/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate killer inhibitory and activating receptor expression by natural killer (NK), natural killer T-like (NKT-like) and CD8+ T lymphocytes in patients with chronic hepatitis C virus (HCV) infection with elevated and with persistently normal alanine aminotransferase (PNALT).
METHODS: The percentage of peripheral blood Treg cells, KIR2DL3, ILT-2, KIR3DL1, CD160, NKG2D, NKG2C expressing NK, T and NKT-like cells, cytokine production and NK cytotoxicity were determined by flow cytometry. Twenty-one patients with chronic HCV infection with elevated alanine aminotransferase, 11 HCV carriers with persistently normal alanine aminotransferase and 15 healthy volunteers were enrolled.
RESULTS: No significant differences were observed in the percentage of total T, NK or NKT-like cells between study groups. Comparing the activating and inhibitory receptor expression by NK cells obtained from HCV carriers with PNALT and chronic HCV hepatitis patients with elevated alanine aminotransferase, NKG2D activating receptor expression was the only receptor showing a significant difference. NKG2D expression of NK cells was significantly lower in patients with elevated alanine aminotransferase. The expression of CD160, NKG2D and NKG2C activating receptor by CD8+ T cells were significantly lower in patients with chronic HCV hepatitis than in healthy controls and in HCV carriers with PNALT. Plasma TGF-β1 levels inversely correlated with NKG2D expression by NK cells. In vitroTGF-β1 treatment inhibited NK cells cytotoxic activity and downregulated NKG2D expression. CD8+ T cells from HCV carriers with PNALT showed significantly elevated expression of CD160, NKG2D and NKG2C activating receptors compared to chronic HCV patients with elevated alanine aminotransferase. Enhanced expression of inhibitory KIR2DL3 receptor, and decreased ILT-2 expression on NK cells were also found in chronic hepatitis C patients compared to healthy controls.
CONCLUSION: Our study demonstrated a complex dysregulation of activating and inhibitory receptor expression, such as decreased NKG2D and CD160 activating receptor expression and increased KIR2DL3 inhibitory receptor expression by NK and cytotoxic T cells and may provide further mechanism contributing to defective cellular immune functions in chronic hepatitis C. Increased NKG2D receptor expression in HCV patients with persistently normal ALT suggests an important pathway for sustaining NK and CD8 T cell function and a protective role against disease progression.
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Hansen SG, Wu HL, Burwitz BJ, Hughes CM, Hammond KB, Ventura AB, Reed JS, Gilbride RM, Ainslie E, Morrow DW, Ford JC, Selseth AN, Pathak R, Malouli D, Legasse AW, Axthelm MK, Nelson JA, Gillespie GM, Walters LC, Brackenridge S, Sharpe HR, López CA, Früh K, Korber BT, McMichael AJ, Gnanakaran S, Sacha JB, Picker LJ. Broadly targeted CD8⁺ T cell responses restricted by major histocompatibility complex E. Science 2016; 351:714-20. [PMID: 26797147 PMCID: PMC4769032 DOI: 10.1126/science.aac9475] [Citation(s) in RCA: 243] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 01/06/2016] [Indexed: 12/22/2022]
Abstract
Major histocompatibility complex E (MHC-E) is a highly conserved, ubiquitously expressed, nonclassical MHC class Ib molecule with limited polymorphism that is primarily involved in the regulation of natural killer (NK) cells. We found that vaccinating rhesus macaques with rhesus cytomegalovirus vectors in which genes Rh157.5 and Rh157.4 are deleted results in MHC-E-restricted presentation of highly varied peptide epitopes to CD8αβ(+) T cells, at ~4 distinct epitopes per 100 amino acids in all tested antigens. Computational structural analysis revealed that MHC-E provides heterogeneous chemical environments for diverse side-chain interactions within a stable, open binding groove. Because MHC-E is up-regulated to evade NK cell activity in cells infected with HIV, simian immunodeficiency virus, and other persistent viruses, MHC-E-restricted CD8(+) T cell responses have the potential to exploit pathogen immune-evasion adaptations, a capability that might endow these unconventional responses with superior efficacy.
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Affiliation(s)
- Scott G. Hansen
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Helen L. Wu
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Benjamin J. Burwitz
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Colette M. Hughes
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Katherine B. Hammond
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Abigail B. Ventura
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Jason S. Reed
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Roxanne M. Gilbride
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Emily Ainslie
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - David W. Morrow
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Julia C. Ford
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Andrea N. Selseth
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Reesab Pathak
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Daniel Malouli
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Alfred W. Legasse
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Michael K. Axthelm
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Jay A. Nelson
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | | | - Lucy C. Walters
- Nuffield Department of Medicine, University of Oxford, OX37FZ, United Kingdom
| | - Simon Brackenridge
- Nuffield Department of Medicine, University of Oxford, OX37FZ, United Kingdom
| | - Hannah R. Sharpe
- Nuffield Department of Medicine, University of Oxford, OX37FZ, United Kingdom
| | - César A. López
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory
| | - Klaus Früh
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Bette T. Korber
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory
- The New Mexico Consortium, Los Alamos, NM 87545
| | - Andrew J. McMichael
- Nuffield Department of Medicine, University of Oxford, OX37FZ, United Kingdom
| | - S. Gnanakaran
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory
| | - Jonah B. Sacha
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
| | - Louis J. Picker
- Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
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Evans TI, Li H, Schafer JL, Klatt NR, Hao XP, Traslavina RP, Estes JD, Brenchley JM, Reeves RK. SIV-induced Translocation of Bacterial Products in the Liver Mobilizes Myeloid Dendritic and Natural Killer Cells Associated With Liver Damage. J Infect Dis 2016; 213:361-9. [PMID: 26238685 PMCID: PMC4704667 DOI: 10.1093/infdis/jiv404] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 07/24/2015] [Indexed: 12/25/2022] Open
Abstract
Disruption of the mucosal epithelium during lentivirus infections permits translocation of microbial products into circulation, causing immune activation and driving disease. Although the liver directly filters blood from the intestine and is the first line of defense against gut-derived antigens, the effects of microbial products on the liver are unclear. In livers of normal macaques, minute levels of bacterial products were detectable, but increased 20-fold in simian immunodeficiency virus (SIV)-infected animals. Increased microbial products in the liver induced production of the chemoattractant CXCL16 by myeloid dendritic cells (mDCs), causing subsequent recruitment of hypercytotoxic natural killer (NK) cells expressing the CXCL16 receptor, CXCR6. Microbial accumulation, mDC activation, and cytotoxic NK cell frequencies were significantly correlated with markers of liver damage, and SIV-infected animals consistently had evidence of hepatitis and fibrosis. Collectively, these data indicate that SIV-associated accumulation of microbial products in the liver initiates a cascade of innate immune activation, resulting in liver damage.
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Affiliation(s)
- Tristan I. Evans
- Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough
| | - Haiying Li
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Jamie L. Schafer
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Nichole R. Klatt
- Department of Pharmaceutics, Washington National Primate Research Center, University of Washington, Seattle
| | - Xing-Pei Hao
- AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory
| | - Ryan P. Traslavina
- AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory
| | - Jacob D. Estes
- AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory
| | - Jason M. Brenchley
- Program in Barrier Immunity and Repair, Immunopathogenesis Section, LMM, NIAID NIH, Bethesda, Maryland
| | - R. Keith Reeves
- Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough
- Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts
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Celik AA, Kraemer T, Huyton T, Blasczyk R, Bade-Döding C. The diversity of the HLA-E-restricted peptide repertoire explains the immunological impact of the Arg107Gly mismatch. Immunogenetics 2016; 68:29-41. [PMID: 26552660 PMCID: PMC4701785 DOI: 10.1007/s00251-015-0880-z] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Accepted: 10/29/2015] [Indexed: 12/21/2022]
Abstract
Human leukocyte antigen (HLA)-E molecules are potent inhibitors of NK cell-mediated killing. Low in polymorphisms, two alleles are widely expressed among diverse populations: HLA-E*01:01 and HLA-E*01:03. Both alleles are distinguished by one SNP resulting in the substitution Arg107Gly. Both alleles present a limited set of peptides derived from class I leader sequences physiologically; however, HLA-E*01:01 presents non-canonical peptides in the absence of HLA class I molecules. To further assess the functional differences between both alleles, we analyzed the peptide repertoire of HLA-E*01:03 by applying soluble HLA technology followed by mass-spectrometric peptide sequencing. HLA-E*01:03 restricted peptides showed a length of 9-17 amino acids and differed in their biophysical properties, no overlap in the peptide repertoire of both allelic variants could be observed; however, both alleles shared marginal peptides from the same proteomic content. Artificial APCs expressing empty HLA-E*01:01 or E*01:03 molecules were generated and stabilized using cognate HLA class I-derived peptide ligands to analyze the impact of residue 107 within the HLA-E heavy chain on the NKG2/CD94 receptor engagement. Differences in peptide stabilization could be translated to the density and half-life time of peptide-HLA-E molecules on the cell surface that subsequently impacted NK cell inhibition as verified by cytotoxicity assays. Taken together, these data illustrate functional differences of HLA-E allelic variants induced by a single amino acid. Furthermore, the function of HLA-E in pathophysiologic situations when the HLA processing machinery is interrupted seems to be more emphasized than previously described, implying a crucial role for HLA-E in tumor or viral immune episodes.
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Affiliation(s)
- Alexander A Celik
- Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor-Lynen-Str. 5, 30625, Hannover, Germany
| | - Thomas Kraemer
- Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor-Lynen-Str. 5, 30625, Hannover, Germany
| | - Trevor Huyton
- Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor-Lynen-Str. 5, 30625, Hannover, Germany
| | - Rainer Blasczyk
- Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor-Lynen-Str. 5, 30625, Hannover, Germany
| | - Christina Bade-Döding
- Institute for Transfusion Medicine, Hannover Medical School, Medical Park, Feodor-Lynen-Str. 5, 30625, Hannover, Germany.
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50
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Camilli G, Cassotta A, Battella S, Palmieri G, Santoni A, Paladini F, Fiorillo MT, Sorrentino R. Regulation and trafficking of the HLA-E molecules during monocyte-macrophage differentiation. J Leukoc Biol 2016; 99:121-30. [PMID: 26310830 DOI: 10.1189/jlb.1a0415-172r] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Accepted: 08/11/2015] [Indexed: 12/20/2022] Open
Abstract
HLA-E is a nonclassical HLA-class I molecule whose best known role is to protect from the natural killer cells. More recently, an additional function more similar to that of classical HLA-class I molecules, i.e., antigen presentation to T cells, is emerging. However, much remains to be explored about the intracellular trafficking of the HLA-E molecules. With the use of 3 different cellular contexts, 2 monocytic cell lines, U937 and THP1, and peripheral blood monocytes, we show here a remarkable increase of HLA-E during monocyte-macrophage differentiation. This goes independently from the classical HLA-class I, the main source of HLA-E-specific peptides, which is found strongly up-regulated upon differentiation of peripheral blood monocytes but not at all in the case of U937 and THP1 cell lines. Although in all cases, there was a moderate increase of HLA-E expressed in the cell surface, lysis by natural killer cells is comparably restored by an anti-NKG2A antibody in untreated as well as in PMA-differentiated U937 cells. Instead, the great majority of the HLA-E is retained in the vesicles of the autophagy-lysosome network, where they colocalize with the microtubule-associated protein light chain 3, as well as with the lysosomal-associated membrane protein 1. We conclude that differently from the classical HLA-class I molecules, the primary destination of the newly synthesized HLA-E molecules in macrophages is, rather than the cell membrane, the intracellular autophagy-lysosomal vesicles where they are stored and where they can encounter the exogenous antigens.
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Affiliation(s)
- Giorgio Camilli
- Departments of *Biology and Biotechnology "Charles Darwin," Experimental Medicine, and Molecular Medicine, and Institute Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy
| | - Antonino Cassotta
- Departments of *Biology and Biotechnology "Charles Darwin," Experimental Medicine, and Molecular Medicine, and Institute Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy
| | - Simone Battella
- Departments of *Biology and Biotechnology "Charles Darwin," Experimental Medicine, and Molecular Medicine, and Institute Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy
| | - Gabriella Palmieri
- Departments of *Biology and Biotechnology "Charles Darwin," Experimental Medicine, and Molecular Medicine, and Institute Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy
| | - Angela Santoni
- Departments of *Biology and Biotechnology "Charles Darwin," Experimental Medicine, and Molecular Medicine, and Institute Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy
| | - Fabiana Paladini
- Departments of *Biology and Biotechnology "Charles Darwin," Experimental Medicine, and Molecular Medicine, and Institute Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy
| | - Maria Teresa Fiorillo
- Departments of *Biology and Biotechnology "Charles Darwin," Experimental Medicine, and Molecular Medicine, and Institute Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy
| | - Rosa Sorrentino
- Departments of *Biology and Biotechnology "Charles Darwin," Experimental Medicine, and Molecular Medicine, and Institute Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, Italy
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