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1
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Ronca V, Gerussi A, Collins P, Parente A, Oo YH, Invernizzi P. The liver as a central "hub" of the immune system: pathophysiological implications. Physiol Rev 2025; 105:493-539. [PMID: 39297676 DOI: 10.1152/physrev.00004.2023] [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: 05/18/2023] [Revised: 09/05/2024] [Accepted: 09/08/2024] [Indexed: 01/16/2025] Open
Abstract
The purpose of this review is to describe the immune function of the liver, guiding the reader from the homeostatic tolerogenic status to the aberrant activation demonstrated in chronic liver disease. An extensive description of the pathways behind the inflammatory modulation of the healthy liver will be provided focusing on the complex immune cell network residing within the liver. The limit of tolerance will be presented in the context of organ transplantation, seizing the limits of homeostatic mechanisms that fail in accepting the graft, progressing eventually toward rejection. The triggers and mechanisms behind chronic activation in metabolic liver conditions and viral hepatitis will be discussed. The last part of the review will be dedicated to one of the greatest paradoxes for a tolerogenic organ, developing autoimmunity. Through the description of the three most common autoimmune liver diseases, the autoimmune reaction against hepatocytes and biliary epithelial cells will be dissected.
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Affiliation(s)
- Vincenzo Ronca
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Humanitas Research Hospital, Milan, Italy
| | - Alessio Gerussi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
| | - Paul Collins
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Faculty of Sciences, Ghent University, Ghent, Belgium
| | - Alessandro Parente
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - Ye Htun Oo
- Centre for Liver and Gastro Research and National Institute for Health and Care Research (NIHR) Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
- Liver Unit, Queen Elizabeth Hospital University Hospital Birmingham National Health Service (NHS) Foundation Trust, Birmingham, United Kingdom
- Centre for Rare Diseases, European Reference Network Centre-Rare Liver, Birmingham, United Kingdom
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, European Reference Network on Hepatological Diseases (ERN RARE-LIVER), IRCCS Fondazione San Gerardo dei Tintori, Monza, Italy
- Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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2
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Guo P, Zhong L, Wang T, Luo W, Zhou A, Cao D. NK cell-based immunotherapy for hepatocellular carcinoma: Challenges and opportunities. Scand J Immunol 2025; 101:e13433. [PMID: 39934640 DOI: 10.1111/sji.13433] [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: 09/07/2024] [Revised: 12/22/2024] [Accepted: 01/01/2025] [Indexed: 02/13/2025]
Abstract
Hepatocellular carcinoma (HCC) remains one of the most challenging malignancies globally, characterized by significant heterogeneity, late-stage diagnosis, and resistance to treatment. In recent years, the advent of immune-checkpoint blockades (ICBs) and targeted immune cell therapies has marked a substantial advancement in HCC treatment. However, the clinical efficacy of these existing therapies is still limited, highlighting the urgent need for new breakthroughs. Natural killer (NK) cells, a subset of the innate lymphoid cell family, have shown unique advantages in the anti-tumour response. With increasing evidence suggesting the crucial role of dysfunctional NK cells in the pathogenesis and progression of HCC, considerable efforts have been directed toward exploring NK cells as a potential therapeutic target for HCC. In this review, we will provide an overview of the role of NK cells in normal liver immunity and in HCC, followed by a detailed discussion of various NK cell-based immunotherapies and their potential applications in HCC treatment.
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Affiliation(s)
- Pei Guo
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Liyuan Zhong
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Tao Wang
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Weijia Luo
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Aiqiang Zhou
- Guangzhou Hospital of Integrated Chinese and Western Medicine, Guangzhou, Guangdong, P.R China
| | - Deliang Cao
- Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang Medical School, University of South China, Hengyang, Hunan, China
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3
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Żychowska J, Ćmil M, Skórka P, Olejnik-Wojciechowska J, Plewa P, Bakinowska E, Kiełbowski K, Pawlik A. The Role of Epigenetic Mechanisms in the Pathogenesis of Hepatitis C Infection. Biomolecules 2024; 14:986. [PMID: 39199374 PMCID: PMC11352264 DOI: 10.3390/biom14080986] [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: 07/11/2024] [Revised: 08/07/2024] [Accepted: 08/08/2024] [Indexed: 09/01/2024] Open
Abstract
Hepatitis C virus (HCV) is a hepatotropic virus that can be transmitted through unsafe medical procedures, such as injections, transfusions, and dental treatment. The infection may be self-limiting or manifest as a chronic form that induces liver fibrosis, cirrhosis, or progression into hepatocellular carcinoma (HCC). Epigenetic mechanisms are major regulators of gene expression. These mechanisms involve DNA methylation, histone modifications, and the activity of non-coding RNAs, which can enhance or suppress gene expression. Abnormal activity or the dysregulated expression of epigenetic molecules plays an important role in the pathogenesis of various pathological disorders, including inflammatory diseases and malignancies. In this review, we summarise the current evidence on epigenetic mechanisms involved in HCV infection and progression to HCC.
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Affiliation(s)
- Justyna Żychowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Maciej Ćmil
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Patryk Skórka
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | | | - Paulina Plewa
- Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland;
| | - Estera Bakinowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Kajetan Kiełbowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (J.Ż.); (M.Ć.); (P.S.); (E.B.); (K.K.)
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4
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Gutiérrez-Iñiguez C, Cervantes-Rodríguez P, González-Hernández LA, Andrade-Villanueva JF, Gutiérrez-Silerio GY, Peña Rodríguez M, Rubio-Sánchez AX, García-Castillo E, Marín-Contreras ME, Del Toro-Arreola S, Bueno-Topete MR, Vega-Magaña N. Unraveling the non-fitness status of NK cells: Examining the NKp30 receptor and its isoforms distribution in HIV/HCV coinfected patients. Mol Immunol 2024; 172:9-16. [PMID: 38850777 DOI: 10.1016/j.molimm.2024.05.010] [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: 12/05/2023] [Revised: 05/23/2024] [Accepted: 05/25/2024] [Indexed: 06/10/2024]
Abstract
BACKGROUND HIV/HCV coinfection is associated with a rapid progression to liver damage. Specifically, NK cell population dysregulation is of particular interest, as these cells have been shown to block HCV replication effectively and have an anti-fibrogenic activity. The NKp30 receptor is linked to tumor cell lysis and has a crucial role during viral infections. In the present study, we determined the subpopulations of NK cells based on CD56 and CD16 expression, NKp30 receptor expression, its isoforms A, B, and C, along with the cytotoxicity molecules in patients with HIV/HCV. RESULTS evidenced by the APRI and FIB-4 indices, the HCV-infected patients presented greater liver damage than the HIV and HIV/HCV groups. The HCV group presented a decreased expression of NKp30 isoform A, and NK cell frequency was not different between groups; however, CD56brigth subpopulation, NKp30 receptor, and CD247 adaptor chain were decreased in HIV/HCV patients; further, we described increased levels of soluble IL-8, IL-10, IL-12, and IL-23 in the serum of HIV/HCV patients. CONCLUSIONS HCV and HIV/HCV patients have multiple parameters of non-fitness status in NK cells; awareness of these dysfunctional immunological parameters in HIV/HCV and HCV patients can elucidate possible novel therapeutics directed towards the improvement of NK cell fitness status, in order to improve their function against liver damage.
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Affiliation(s)
- Cecilia Gutiérrez-Iñiguez
- Maestría en Microbiología Médica, CUCS, Universidad de Guadalajara, Guadalajara, Jalisco CP.44340, Mexico
| | - Paulina Cervantes-Rodríguez
- Centro Universitario de Ciencias Exactas e Ingeniería, Universidad de Guadalajara, Guadalajara, Jalisco CP.44430, Mexico
| | - Luz Alicia González-Hernández
- Unidad de VIH del Antiguo Hospital Civil "Fray Antonio Alcalde", Guadalajara, Jalisco CP.44200, Mexico; Instituto de Investigación en Inmunodeficiencias y VIH (InIVIH), CUCS, Universidad de Guadalajara, Guadalajara, Jalisco CP.44200, Mexico
| | | | - Gloria Yareli Gutiérrez-Silerio
- Laboratorio de endocrinología y nutrición, Facultad de Medicina de la Universidad Autónoma de Querétaro, Querétaro CP.76140, Mexico
| | - Marcela Peña Rodríguez
- Laboratorio de Diagnóstico de Enfermedades Emergentes y Reemergentes (LaDEER), CUCS, Universidad de Guadalajara, Guadalajara, Jalisco CP.44340, Mexico
| | - Alina Xcaret Rubio-Sánchez
- Maestría en Microbiología Médica, CUCS, Universidad de Guadalajara, Guadalajara, Jalisco CP.44340, Mexico
| | - Estefania García-Castillo
- Unidad Médica de Alta Especialidad, Hospital de Especialidades, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco CP.44340, Mexico
| | - María Eugenia Marín-Contreras
- Unidad Médica de Alta Especialidad, Hospital de Especialidades, Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco CP.44340, Mexico
| | - Susana Del Toro-Arreola
- Instituto de Investigación en Enfermedades Crónico Degenerativas (IECD), CUCS, Universidad de Guadalajara, Guadalajara, Jalisco CP.44340, Mexico
| | - Miriam Ruth Bueno-Topete
- Instituto de Investigación en Enfermedades Crónico Degenerativas (IECD), CUCS, Universidad de Guadalajara, Guadalajara, Jalisco CP.44340, Mexico
| | - Natali Vega-Magaña
- Laboratorio de Diagnóstico de Enfermedades Emergentes y Reemergentes (LaDEER), CUCS, Universidad de Guadalajara, Guadalajara, Jalisco CP.44340, Mexico; Instituto de Investigación en Ciencias Biomédicas (IICB), CUCS, Universidad de Guadalajara, Mexico.
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Lenart M, Rutkowska-Zapała M, Siedlar M. NK-cell receptor modulation in viral infections. Clin Exp Immunol 2024; 217:151-158. [PMID: 38767592 PMCID: PMC11239562 DOI: 10.1093/cei/uxae045] [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: 02/02/2024] [Accepted: 05/17/2024] [Indexed: 05/22/2024] Open
Abstract
Natural killer (NK) cells play a crucial role in controlling viral infections. The ability to kill infected cells without prior immunization, yet being tolerant to self, healthy cells, depends on the balance of germ-line encoded surface receptors. NK-cell receptors are divided into either activating, leading to activation of NK cell and its cytotoxic and pro-inflammatory activity, or inhibitory, providing tolerance for a target cell. The signals from inhibitory receptors dominate and NK-cell activation requires stimulation of activating receptors. In viral infections, NK-cell interaction with infected cells can result in activation, memory-like NK-cell differentiation, or NK-cell exhaustion, which constitutes one of the viral immune evasion mechanisms. All of these states are associated with the modulation of NK-cell receptor expression. In this review, we summarize the current knowledge of NK-cell receptors and their role in viral infection control, as well as the alterations of their expression observed in acute or chronic infections. We present recently discovered SARS-CoV-2-mediated modulation of NK-cell receptor expression and compare them with other human viral infections. Finally, since modulation of NK-cell receptor activation gives a promising addition to currently used antiviral therapies, we briefly discuss the clinical significance and future perspective of the application of agonists or antagonists of activating and inhibitory receptors, respectively. In sum, our review shows that although much is known about NK-cell receptor biology, a deeper understanding of NK-cell receptors role in viral infections is still needed.
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Affiliation(s)
- Marzena Lenart
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka, Krakow, Poland
| | - Magdalena Rutkowska-Zapała
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka, Krakow, Poland
| | - Maciej Siedlar
- Department of Clinical Immunology, Institute of Pediatrics, Jagiellonian University Medical College, Wielicka, Krakow, Poland
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6
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Bi W, Kraft A, Engelskircher S, Mischke J, Witte M, Klawonn F, van Ham M, Cornberg M, Wedemeyer H, Hengst J, Jänsch L. Proteomics reveals a global phenotypic shift of NK cells in HCV patients treated with direct-acting antivirals. Eur J Immunol 2023; 53:e2250291. [PMID: 37515498 DOI: 10.1002/eji.202250291] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 07/28/2023] [Accepted: 07/28/2023] [Indexed: 07/31/2023]
Abstract
Chronic hepatitis C virus (HCV) infections compromise natural killer (NK)-cell immunity. Direct-acting antivirals (DAA) effectively eliminate HCV, but the long-term effects on NK cells in cured patients are debated. We conducted a proteomic study on CD56+ NK cells of chronic HCV-infected patients before and 1 year after DAA therapy. Donor-variation was observed in NK-cell proteomes of HCV-infected patients, with 46 dysregulated proteins restored after DAA therapy. However, 30% of the CD56+ NK-cell proteome remained altered 1 year post-therapy, indicating a phenotypic shift with low donor-variation. NK cells from virus-negative cured patients exhibited global regulation of RNA-processing and pathways related to "stimuli response", "chemokine signaling", and "cytotoxicity regulation". Proteomics identified downregulation of vesicle transport components (CD107a, COPI/II complexes) and altered receptor expression profiles, indicating an inhibited NK-cell phenotype. Yet, activated NK cells from HCV patients before and after therapy effectively upregulated IFN-γ and recruited CD107a. Conversely, reduced surface expression levels of Tim-3 and 2B4 were observed before and after therapy. In conclusion, this study reveals long-term effects on the CD56+ NK-cell compartment in convalescent HCV patients 1 year after therapy, with limited abundance of vesicle transport complexes and surface receptors, associated with a responsive NK-cell phenotype.
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Affiliation(s)
- Wenjie Bi
- Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, P. R. China
- Cellular Proteome Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Anke Kraft
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), A Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- German Centre for Infection Research (DZIF), Partner site Hannover-Braunschweig, Hannover, Germany
- TWINCORE, A Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Sophie Engelskircher
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), A Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
| | - Jasmin Mischke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), A Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- German Centre for Infection Research (DZIF), Partner site Hannover-Braunschweig, Hannover, Germany
- TWINCORE, A Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Moana Witte
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), A Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
| | - Frank Klawonn
- Cellular Proteome Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
- Department of Computer Science, Ostfalia University, Wolfenbüttel, Germany
| | - Marco van Ham
- Cellular Proteome Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Markus Cornberg
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
- Centre for Individualised Infection Medicine (CiiM), A Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- German Centre for Infection Research (DZIF), Partner site Hannover-Braunschweig, Hannover, Germany
- TWINCORE, A Joint Venture Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany
| | - Heiner Wedemeyer
- Centre for Individualised Infection Medicine (CiiM), A Joint Venture Between the Helmholtz Centre for Infection Research (HZI) and Hannover Medical School (MHH), Hannover, Germany
- German Centre for Infection Research (DZIF), Partner site Hannover-Braunschweig, Hannover, Germany
- Cluster of Excellence Resolving Infection Susceptibility (RESIST; EXC 2155), Hannover Medical School, Hannover, Germany
| | - Julia Hengst
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School (MHH), Hannover, Germany
| | - Lothar Jänsch
- Cellular Proteome Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
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7
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Mak ML, Reid KT, Crome SQ. Protective and pathogenic functions of innate lymphoid cells in transplantation. Clin Exp Immunol 2023; 213:23-39. [PMID: 37119279 PMCID: PMC10324558 DOI: 10.1093/cei/uxad050] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 03/27/2023] [Accepted: 04/28/2023] [Indexed: 05/01/2023] Open
Abstract
Innate lymphoid cells (ILCs) are a family of lymphocytes with essential roles in tissue homeostasis and immunity. Along with other tissue-resident immune populations, distinct subsets of ILCs have important roles in either promoting or inhibiting immune tolerance in a variety of contexts, including cancer and autoimmunity. In solid organ and hematopoietic stem cell transplantation, both donor and recipient-derived ILCs could contribute to immune tolerance or rejection, yet understanding of protective or pathogenic functions are only beginning to emerge. In addition to roles in directing or regulating immune responses, ILCs interface with parenchymal cells to support tissue homeostasis and even regeneration. Whether specific ILCs are tissue-protective or enhance ischemia reperfusion injury or fibrosis is of particular interest to the field of transplantation, beyond any roles in limiting or promoting allograft rejection or graft-versus host disease. Within this review, we discuss the current understanding of ILCs functions in promoting immune tolerance and tissue repair at homeostasis and in the context of transplantation and highlight where targeting or harnessing ILCs could have applications in novel transplant therapies.
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Affiliation(s)
- Martin L Mak
- Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
- Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, Canada
| | - Kyle T Reid
- Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
- Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, Canada
| | - Sarah Q Crome
- Department of Immunology, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
- Toronto General Hospital Research Institute, Ajmera Transplant Centre, University Health Network, Toronto, Canada
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8
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De Re V, Tornesello ML, Racanelli V, Prete M, Steffan A. Non-Classical HLA Class 1b and Hepatocellular Carcinoma. Biomedicines 2023; 11:1672. [PMID: 37371767 PMCID: PMC10296335 DOI: 10.3390/biomedicines11061672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 06/02/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
A number of studies are underway to gain a better understanding of the role of immunity in the pathogenesis of hepatocellular carcinoma and to identify subgroups of individuals who may benefit the most from systemic therapy according to the etiology of their tumor. Human leukocyte antigens play a key role in antigen presentation to T cells. This is fundamental to the host's defense against pathogens and tumor cells. In addition, HLA-specific interactions with innate lymphoid cell receptors, such those present on natural killer cells and innate lymphoid cell type 2, have been shown to be important activators of immune function in the context of several liver diseases. More recent studies have highlighted the key role of members of the non-classical HLA-Ib and the transcript adjacent to the HLA-F locus, FAT10, in hepatocarcinoma. The present review analyzes the major contribution of these molecules to hepatic viral infection and hepatocellular prognosis. Particular attention has been paid to the association of natural killer and Vδ2 T-cell activation, mediated by specific HLA class Ib molecules, with risk assessment and novel treatment strategies to improve immunotherapy in HCC.
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Affiliation(s)
- Valli De Re
- Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), 33081 Aviano, Italy;
| | - Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, 80131 Naples, Italy;
| | - Vito Racanelli
- Department of Interdisciplinary Medicine, School of Medicine, ‘Aldo Moro’ University of Bari, 70124 Bari, Italy; (V.R.); (M.P.)
| | - Marcella Prete
- Department of Interdisciplinary Medicine, School of Medicine, ‘Aldo Moro’ University of Bari, 70124 Bari, Italy; (V.R.); (M.P.)
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), 33081 Aviano, Italy;
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9
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Wang L, Chen Z, Liu G, Pan Y. Functional crosstalk and regulation of natural killer cells in tumor microenvironment: Significance and potential therapeutic strategies. Genes Dis 2023; 10:990-1004. [PMID: 37396514 PMCID: PMC10308134 DOI: 10.1016/j.gendis.2022.07.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/11/2022] [Accepted: 07/15/2022] [Indexed: 11/19/2022] Open
Abstract
Natural killer (NK) cells eliminate a large variety of tumor cells and abnormal cells. However, NK cells in the tumor microenvironment (TME) are often functionally depleted. A few subsets of NK cells even promote tumor growth. This study reviewed the biological properties of NK cells, the dynamic phenotypic changes of NK cells in the TME, and the communication between NK cells and other immune and nonimmune cells.
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Affiliation(s)
- Liping Wang
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China
| | - Zhe Chen
- Department of Otolaryngology Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China
| | - Guohong Liu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China
| | - Yunbao Pan
- Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei 430071, China
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10
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Zafarani A, Razizadeh MH, Pashangzadeh S, Amirzargar MR, Taghavi-Farahabadi M, Mahmoudi M. Natural killer cells in COVID-19: from infection, to vaccination and therapy. Future Virol 2023:10.2217/fvl-2022-0040. [PMID: 36936055 PMCID: PMC10013930 DOI: 10.2217/fvl-2022-0040] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 01/31/2023] [Indexed: 03/15/2023]
Abstract
Natural killer (NK) cells are among the most important innate immunity members, which are the first cells that fight against infected cells. The function of these cells is impaired in patients with COVID-19 and they are not able to prevent the spread of the disease or destroy the infected cells. Few studies have evaluated the effects of COVID-19 vaccines on NK cells, though it has been demonstrated that DNA vaccines and BNT162b2 can affect NK cell response. In the present paper, the effects of SARS-CoV-2 on the NK cells during infection, the effect of vaccination on NK cells, and the NK cell-based therapies were reviewed.
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Affiliation(s)
- Alireza Zafarani
- 1Department of Hematology & Blood Banking, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Salar Pashangzadeh
- 3Iranian Research Center for HIV/AIDS, Iranian Institute for Reduction of High-Risk Behaviors, Tehran University of Medical Sciences, Tehran, Iran
- 4Immunology Today, Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Mohammad Reza Amirzargar
- 1Department of Hematology & Blood Banking, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Taghavi-Farahabadi
- 5Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Mahmoudi
- 6Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, 1449614535, Iran
- Author for correspondence: Tel.: +98 936 002 0731;
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Fodor M, Salcher S, Gottschling H, Mair A, Blumer M, Sopper S, Ebner S, Pircher A, Oberhuber R, Wolf D, Schneeberger S, Hautz T. The liver-resident immune cell repertoire - A boon or a bane during machine perfusion? Front Immunol 2022; 13:982018. [PMID: 36311746 PMCID: PMC9609784 DOI: 10.3389/fimmu.2022.982018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/30/2022] [Indexed: 11/13/2022] Open
Abstract
The liver has been proposed as an important “immune organ” of the body, as it is critically involved in a variety of specific and unique immune tasks. It contains a huge resident immune cell repertoire, which determines the balance between tolerance and inflammation in the hepatic microenvironment. Liver-resident immune cells, populating the sinusoids and the space of Disse, include professional antigen-presenting cells, myeloid cells, as well as innate and adaptive lymphoid cell populations. Machine perfusion (MP) has emerged as an innovative technology to preserve organs ex vivo while testing for organ quality and function prior to transplantation. As for the liver, hypothermic and normothermic MP techniques have successfully been implemented in clinically routine, especially for the use of marginal donor livers. Although there is evidence that ischemia reperfusion injury-associated inflammation is reduced in machine-perfused livers, little is known whether MP impacts the quantity, activation state and function of the hepatic immune-cell repertoire, and how this affects the inflammatory milieu during MP. At this point, it remains even speculative if liver-resident immune cells primarily exert a pro-inflammatory and hence destructive effect on machine-perfused organs, or in part may be essential to induce liver regeneration and counteract liver damage. This review discusses the role of hepatic immune cell subtypes during inflammatory conditions and ischemia reperfusion injury in the context of liver transplantation. We further highlight the possible impact of MP on the modification of the immune cell repertoire and its potential for future applications and immune modulation of the liver.
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Affiliation(s)
- M. Fodor
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Salcher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - H. Gottschling
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Mair
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - M. Blumer
- Department of Anatomy and Embryology, Medical University of Innsbruck, Innsbruck, Austria
| | - S. Sopper
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Ebner
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - A. Pircher
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - R. Oberhuber
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - D. Wolf
- Department of Internal Medicine V, Hematology and Oncology, Comprehensive Cancer Center Innsbruck (CCCI), Medical University Innsbruck (MUI), Innsbruck, Austria
| | - S. Schneeberger
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
| | - T. Hautz
- Department of Visceral, Transplant and Thoracic Surgery, Center of Operative Medicine, organLife Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- Department of Visceral, Transplant and Thoracic Surgery, Daniel Swarovski Research Laboratory, Medical University of Innsbruck, Innsbruck, Austria
- *Correspondence: T. Hautz,
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12
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Moll-Bernardes R, Fortier SC, Sousa AS, Lopes RD, Vera N, Conde L, Feldman A, Arruda G, Cabral-Castro M, Albuquerque DC, Paula TC, Furquim T, Loures VA, Giusti K, Oliveira N, Macedo A, Barros e Silva P, De Luca F, Kotsugai M, Domiciano R, Silva FA, Santos MF, Souza OF, Bozza FA, Luiz RR, Medei E. NKG2A Expression among CD8 Cells Is Associated with COVID-19 Progression in Hypertensive Patients: Insights from the BRACE CORONA Randomized Trial. J Clin Med 2022; 11:jcm11133713. [PMID: 35806995 PMCID: PMC9267446 DOI: 10.3390/jcm11133713] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/23/2022] [Accepted: 06/23/2022] [Indexed: 12/15/2022] Open
Abstract
Cardiovascular comorbidities and immune-response dysregulation are associated with COVID-19 severity. We aimed to explore the key immune cell profile and understand its association with disease progression in 156 patients with hypertension that were hospitalized due to COVID-19. The primary outcome was progression to severe disease. The probability of progression to severe disease was estimated using a logistic regression model that included clinical variables and immune cell subsets associated with the primary outcome. Obesity; diabetes; oxygen saturation; lung involvement on computed tomography (CT) examination; the C-reactive protein concentration; total lymphocyte count; proportions of CD4+ and CD8+ T cells; CD4/CD8 ratio; CD8+ HLA-DR MFI; and CD8+ NKG2A MFI on admission were all associated with progression to severe COVID-19. This study demonstrated that increased CD8+ NKG2A MFI at hospital admission, in combination with some clinical variables, is associated with a high risk of COVID-19 progression in hypertensive patients. These findings reinforce the hypothesis of the functional exhaustion of T cells with the increased expression of NKG2A in patients with severe COVID-19, elucidating how severe acute respiratory syndrome coronavirus 2 infection may break down the innate antiviral immune response at an early stage of the disease, with future potential therapeutic implications.
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Affiliation(s)
- Renata Moll-Bernardes
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
| | - Sérgio C. Fortier
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Pathological Anatomy Laboratory, Rede D’Or São Luiz, São Paulo 04321-120, Brazil
| | - Andréa S. Sousa
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil
| | - Renato D. Lopes
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27710, USA
- Brazilian Clinical Research Institute, São Paulo 01404-000, Brazil;
| | - Narendra Vera
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-170, Brazil; (N.V.); (L.C.)
| | - Luciana Conde
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-170, Brazil; (N.V.); (L.C.)
| | - André Feldman
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- São Luiz Anália Franco Hospital, São Paulo 03313-001, Brazil
| | - Guilherme Arruda
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- São Luiz São Caetano Hospital, São Caetano do Sul 09531-205, Brazil
| | - Mauro Cabral-Castro
- Institute of Microbiology Paulo de Góes, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil;
| | - Denílson C. Albuquerque
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Cardiology Department, Rio de Janeiro State University, Rio de Janeiro 20551-030, Brazil
| | - Thiago C. Paula
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- São Luiz Jabaquara Hospital, São Paulo 04321-120, Brazil
| | - Thyago Furquim
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Sino Brasileiro Hospital, Osasco 06016-050, Brazil
| | - Vitor A. Loures
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- São Luiz Anália Franco Hospital, São Paulo 03313-001, Brazil
| | - Karla Giusti
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Villa Lobos Hospital, São Paulo 03184-020, Brazil
| | - Nathália Oliveira
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Villa Lobos Hospital, São Paulo 03184-020, Brazil
| | - Ariane Macedo
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- São Luiz Jabaquara Hospital, São Paulo 04321-120, Brazil
- Santa Casa of São Paulo, São Paulo 01221-010, Brazil
| | | | - Fábio De Luca
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- São Luiz Morumbi Hospital, São Paulo 05605-050, Brazil
| | - Marisol Kotsugai
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- São Luiz Morumbi Hospital, São Paulo 05605-050, Brazil
| | - Rafael Domiciano
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- São Luiz Anália Franco Hospital, São Paulo 03313-001, Brazil
| | - Flávia A. Silva
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Pathological Anatomy Laboratory, Rede D’Or São Luiz, São Paulo 04321-120, Brazil
| | - Mayara F. Santos
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
| | - Olga F. Souza
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Copa Star Hospital, Rio de Janeiro 22031-012, Brazil
| | - Fernando A. Bozza
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil
| | - Ronir R. Luiz
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Public Health Studies Institute—IESC, Federal University of Rio de Janeiro, Rio de Janeiro 21941-592, Brazil
| | - Emiliano Medei
- D’Or Institute for Research and Education, Rio de Janeiro 22281-100, Brazil; (R.M.-B.); (S.C.F.); (A.S.S.); (R.D.L.); (A.F.); (G.A.); (D.C.A.); (T.C.P.); (T.F.); (V.A.L.); (K.G.); (N.O.); (A.M.); (F.D.L.); (M.K.); (R.D.); (F.A.S.); (M.F.S.); (O.F.S.); (F.A.B.); (R.R.L.)
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-170, Brazil; (N.V.); (L.C.)
- National Center for Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Correspondence: ; Tel.: +55-21-3938-0370
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13
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Murphy JM, Ngai L, Mortha A, Crome SQ. Tissue-Dependent Adaptations and Functions of Innate Lymphoid Cells. Front Immunol 2022; 13:836999. [PMID: 35359972 PMCID: PMC8960279 DOI: 10.3389/fimmu.2022.836999] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/11/2022] [Indexed: 12/21/2022] Open
Abstract
Tissue-resident immune cells reside in distinct niches across organs, where they contribute to tissue homeostasis and rapidly respond to perturbations in the local microenvironment. Innate lymphoid cells (ILCs) are a family of innate immune cells that regulate immune and tissue homeostasis. Across anatomical locations throughout the body, ILCs adopt tissue-specific fates, differing from circulating ILC populations. Adaptations of ILCs to microenvironmental changes have been documented in several inflammatory contexts, including obesity, asthma, and inflammatory bowel disease. While our understanding of ILC functions within tissues have predominantly been based on mouse studies, development of advanced single cell platforms to study tissue-resident ILCs in humans and emerging patient-based data is providing new insights into this lymphocyte family. Within this review, we discuss current concepts of ILC fate and function, exploring tissue-specific functions of ILCs and their contribution to health and disease across organ systems.
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Affiliation(s)
- Julia M. Murphy
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
| | - Louis Ngai
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Arthur Mortha
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Sarah Q. Crome
- Department of Immunology, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Ajmera Transplant Centre, University Health Network, Toronto, ON, Canada
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14
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Zaki MYW, Fathi AM, Samir S, Eldafashi N, William KY, Nazmy MH, Fathy M, Gill US, Shetty S. Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:1255. [PMID: 35267563 PMCID: PMC8909759 DOI: 10.3390/cancers14051255] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 02/08/2023] Open
Abstract
Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients.
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Affiliation(s)
- Marco Y. W. Zaki
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Ahmed M. Fathi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Samara Samir
- Department of Biochemistry, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt;
| | - Nardeen Eldafashi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Kerolis Y. William
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 12613, Egypt;
| | - Maiiada Hassan Nazmy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Upkar S. Gill
- Barts Liver Centre, Centre for Immunobiology, Barts & The London School of Medicine & Dentistry, QMUL, London E1 2AT, UK;
| | - Shishir Shetty
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
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15
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Martinez-Espinosa I, Serrato JA, Ortiz-Quintero B. Role of IL-10-Producing Natural Killer Cells in the Regulatory Mechanisms of Inflammation during Systemic Infection. Biomolecules 2021; 12:biom12010004. [PMID: 35053151 PMCID: PMC8773486 DOI: 10.3390/biom12010004] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Revised: 12/08/2021] [Accepted: 12/11/2021] [Indexed: 12/29/2022] Open
Abstract
Natural killer (NK) cells have the dual ability to produce pro-inflammatory (IFNγ) and anti-inflammatory (IL-10) cytokines during systemic infection, which points to their crucial role both as inflammatory effectors for infection clearance and as regulators to counterbalance inflammation to limit immune-mediated damage to the host. In particular, immunosuppressive IL-10 secretion by NK cells has been described to occur in systemic, but not local, infections as a recent immunoregulatory mechanism of inflammation that may be detrimental or beneficial, depending on the timing of release, type of disease, or the infection model. Understanding the factors that drive the production of IL-10 by NK cells and their impact during dualistic inflammatory states, such as sepsis and other non-controlled inflammatory diseases, is relevant for achieving effective therapeutic advancements. In this review, the evidence regarding the immunoregulatory role of IL-10-producing NK cells in systemic infection is summarized and discussed in detail, and the potential molecular mechanisms that drive IL-10 production by NK cells are considered.
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16
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Zhou J, Zhang S, Guo C. Crosstalk between macrophages and natural killer cells in the tumor microenvironment. Int Immunopharmacol 2021; 101:108374. [PMID: 34824036 DOI: 10.1016/j.intimp.2021.108374] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 12/17/2022]
Abstract
The tumor microenvironment (TME) is jointly constructed by a variety of cell types, including tumor cells, immune cells, fibroblasts, and epithelial cells, among others. The cells within the TME interact with each other and with tumor cells to influence tumor development and progression. As the most abundant immune cells in the TME, macrophages regulate the immune network by not only secreting a large amount of versatile cytokines but also expressing a series of ligands or receptors on the surface to interact with other cells directly. Due to their strong plasticity, they exert both immunostimulatory and immunosuppressive effects in the complex TME. The major effector cells of the immune system that directly target cancer cells include but are not limited to natural killer cells (NKs), dendritic cells (DCs), macrophages, polymorphonuclear leukocytes, mast cells, and cytotoxic T lymphocytes (CTLs). Among them, NK cells are the predominant innate lymphocyte subsets that mediate antitumor and antiviral responses. The activation and inhibition of NK cells are regulated by cytokines and the balance between activating and inhibitory receptors. There is an inextricable regulatory relationship between macrophages and NK cells. Herein, we systematically elaborate on the regulatory network between macrophages and NK cells through soluble mediator crosstalk and cell-to-cell interactions. We believe that a better understanding of the crosstalk between macrophages and NKs in the TME will benefit the development of novel macrophage- or NK cell-focused therapeutic strategies with superior efficacies in cancer therapy.
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Affiliation(s)
- Jingping Zhou
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China
| | - Shaolong Zhang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China
| | - Changying Guo
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, PR China.
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17
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Highton AJ, Schuster IS, Degli-Esposti MA, Altfeld M. The role of natural killer cells in liver inflammation. Semin Immunopathol 2021; 43:519-533. [PMID: 34230995 PMCID: PMC8260327 DOI: 10.1007/s00281-021-00877-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/03/2021] [Indexed: 02/07/2023]
Abstract
The liver is an important immunological site that can promote immune tolerance or activation. Natural killer (NK) cells are a major immune subset within the liver, and therefore understanding their role in liver homeostasis and inflammation is crucial. Due to their cytotoxic function, NK cells are important in the immune response against hepatotropic viral infections but are also involved in the inflammatory processes of autoimmune liver diseases and fatty liver disease. Whether NK cells primarily promote pro-inflammatory or tolerogenic responses is not known for many liver diseases. Understanding the involvement of NK cells in liver inflammation will be crucial in effective treatment and future immunotherapeutic targeting of NK cells in these disease settings. Here, we explore the role that NK cells play in inflammation of the liver in the context of viral infection, autoimmunity and fatty liver disease.
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Affiliation(s)
- A J Highton
- Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany
| | - I S Schuster
- Experimental and Viral Immunology, Department of Microbiology and Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Experimental Immunology, Lions Eye Institute, Perth, Western Australia, Australia
| | - M A Degli-Esposti
- Experimental and Viral Immunology, Department of Microbiology and Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.,Experimental Immunology, Lions Eye Institute, Perth, Western Australia, Australia
| | - M Altfeld
- Institute for Immunology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
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18
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Marofi F, Al-Awad AS, Sulaiman Rahman H, Markov A, Abdelbasset WK, Ivanovna Enina Y, Mahmoodi M, Hassanzadeh A, Yazdanifar M, Stanley Chartrand M, Jarahian M. CAR-NK Cell: A New Paradigm in Tumor Immunotherapy. Front Oncol 2021; 11:673276. [PMID: 34178661 PMCID: PMC8223062 DOI: 10.3389/fonc.2021.673276] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/14/2021] [Indexed: 12/15/2022] Open
Abstract
The tumor microenvironment (TME) is greatly multifaceted and immune escape is an imperative attribute of tumors fostering tumor progression and metastasis. Based on reports, the restricted achievement attained by T cell immunotherapy reflects the prominence of emerging other innovative immunotherapeutics, in particular, natural killer (NK) cells-based treatments. Human NK cells act as the foremost innate immune effector cells against tumors and are vastly heterogeneous in the TME. Currently, there exists a rapidly evolving interest in the progress of chimeric antigen receptor (CAR)-engineered NK cells for tumor immunotherapy. CAR-NK cells superiorities over CAR-T cells in terms of better safety (e.g., absence or minimal cytokine release syndrome (CRS) and graft-versus-host disease (GVHD), engaging various mechanisms for stimulating cytotoxic function, and high feasibility for 'off-the-shelf' manufacturing. These effector cells could be modified to target various antigens, improve proliferation and persistence in vivo, upturn infiltration into tumors, and defeat resistant TME, which in turn, result in a desired anti-tumor response. More importantly, CAR-NK cells represent antigen receptors against tumor-associated antigens (TAAs), thereby redirecting the effector NK cells and supporting tumor-related immunosurveillance. In the current review, we focus on recent progress in the therapeutic competence of CAR-NK cells in solid tumors and offer a concise summary of the present hurdles affecting therapeutic outcomes of CAR-NK cell-based tumor immunotherapies.
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Affiliation(s)
- Faroogh Marofi
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Heshu Sulaiman Rahman
- College of Medicine, University of Sulaimani, Sulaymaniyah, Iraq
- Department of Medical Laboratory Sciences, Komar University of Science and Technology, Sulaymaniyah, Iraq
| | - Alexander Markov
- Tyumen State Medical University, Tyumen, Russia
- Tyumen Industrial University, Tyumen, Russia
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | | | - Mahnaz Mahmoodi
- Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Ali Hassanzadeh
- Department of Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahboubeh Yazdanifar
- Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, CA, United States
| | | | - Mostafa Jarahian
- German Cancer Research Center, Toxicology and Chemotherapy Unit (G401), Heidelberg, Germany
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19
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Jacobs B, Gebel V, Heger L, Grèze V, Schild H, Dudziak D, Ullrich E. Characterization and Manipulation of the Crosstalk Between Dendritic and Natural Killer Cells Within the Tumor Microenvironment. Front Immunol 2021; 12:670540. [PMID: 34054844 PMCID: PMC8160470 DOI: 10.3389/fimmu.2021.670540] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 04/19/2021] [Indexed: 01/22/2023] Open
Abstract
Cellular therapy has entered the daily clinical life with the approval of CAR T cell therapeutics and dendritic cell (DCs) vaccines in the US and the EU. In addition, numerous other adoptive cellular products, including natural killer (NK) cells, are currently evaluated in early phase I/ II clinical trials for the treatment of cancer patients. Despite these promising accomplishments, various challenges remain to be mastered in order to ensure sustained therapeutic success. These include the identification of strategies by which tumor cells escape the immune system or establish an immunosuppressive tumor microenvironment (TME). As part of the innate immune system, DCs and NK cells are both present within the TME of various tumor entities. While NK cells are well known for their intrinsic anti-tumor activity by their cytotoxicity capacities and the secretion of pro-inflammatory cytokines, the role of DCs within the TME is a double-edged sword as different DC subsets have been described with either tumor-promoting or -inhibiting characteristics. In this review, we will discuss recent findings on the interaction of DCs and NK cells under physiological conditions and within the TME. One focus is the crosstalk of various DC subsets with NK cells and their impact on the progression or inhibition of tumor growth. In addition, we will provide suggestions to overcome the immunosuppressive outcome of the interaction of DCs and NK cells within the TME.
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Affiliation(s)
- Benedikt Jacobs
- Department of Internal Medicine 5, Haematology and Oncology, Friedrich Alexander University Erlangen-Nuremberg (FAU), University Hospital Erlangen, Erlangen, Germany
| | - Veronika Gebel
- Children's Hospital, Goethe-University Frankfurt, Frankfurt, Germany.,Experimental Immunology, Goethe University Frankfurt , Frankfurt, Germany.,Frankfurt Cancer Institute, Goethe University, Frankfurt, Germany
| | - Lukas Heger
- Department of Dermatology, Laboratory of Dendritic Cell Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Victoria Grèze
- Children's Hospital, Goethe-University Frankfurt, Frankfurt, Germany.,Experimental Immunology, Goethe University Frankfurt , Frankfurt, Germany.,Frankfurt Cancer Institute, Goethe University, Frankfurt, Germany
| | - Hansjörg Schild
- Institute of Immunology, University Medical Center Mainz, Mainz, Germany.,Research Centre for Immunotherapy, University Medical Center Mainz, Mainz, Germany
| | - Diana Dudziak
- Department of Dermatology, Laboratory of Dendritic Cell Biology, University Hospital Erlangen and Friedrich-Alexander University Erlangen-Nuremberg (FAU), Erlangen, Germany
| | - Evelyn Ullrich
- Children's Hospital, Goethe-University Frankfurt, Frankfurt, Germany.,Experimental Immunology, Goethe University Frankfurt , Frankfurt, Germany.,Frankfurt Cancer Institute, Goethe University, Frankfurt, Germany
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20
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Natural Killer-Dendritic Cell Interactions in Liver Cancer: Implications for Immunotherapy. Cancers (Basel) 2021; 13:cancers13092184. [PMID: 34062821 PMCID: PMC8124166 DOI: 10.3390/cancers13092184] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/22/2021] [Accepted: 04/29/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The reciprocal crosstalk between dendritic cells (DCs) and natural killer (NK) cells plays a pivotal role in regulating immune defense against viruses and tumors. The Th-cell polarizing ability, cytokine-producing capacity, chemokine expression, and migration of DCs are regulated by activated NK cells. Conversely, the effector functions including lysis and cytokine production, proliferation, and migration of NK cells are influenced by close interactions with activated DCs. In this review, we explore the impact of DC–NK cell crosstalk and its therapeutic potential in immune control of liver malignances. Abstract Natural killer (NK) and dendritic cells (DCs) are innate immune cells that play a crucial role in anti-tumor immunity. NK cells kill tumor cells through direct cytotoxicity and cytokine secretion. DCs are needed for the activation of adaptive immune responses against tumor cells. Both NK cells and DCs are subdivided in several subsets endowed with specialized effector functions. Crosstalk between NK cells and DCs leads to the reciprocal control of their activation and polarization of immune responses. In this review, we describe the role of NK cells and DCs in liver cancer, focusing on the mechanisms involved in their reciprocal control and activation. In this context, intrahepatic NK cells and DCs present unique immunological features, due to the constant exposure to non-self-circulating antigens. These interactions might play a fundamental role in the pathology of primary liver cancer, namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). Additionally, the implications of these immune changes are relevant from the perspective of improving the cancer immunotherapy strategies in HCC and ICC patients.
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21
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Abstract
Hepatitis C virus (HCV) is a small positive-sense, single-stranded RNA virus, the causal organism for chronic hepatitis. Chronic hepatitis leads to inflammation of liver, causing cirrhosis, fibrosis and steatosis, which may ultimately lead to liver cancer in a few cases. Innate and adaptive immune responses play an important role in the pathogenesis of HCV infection, thus acting as an important component in deciding the fate of the disease. Numerous studies have indicated that the derangement of these immune responses results in the persistence of infection leading to chronic state of the disease. Interactions between virus and host immune system generally result in the elimination of virus, but as the virus evolves with different evading mechanisms, it makes environment favourable for its survival and replication. It has been reported that HCV impairs the immune system by functional modulation of the cells of innate as well as adaptive immune responses, resulting in chronic state of the disease, influencing the response to antiviral therapy in these patients. These defects in the immune system lead to suboptimal immune responses and therefore, impaired effector functions. This review highlights the involvement or association of different immune cells such as natural killer cells, B cells, dendritic cells and T cells in HCV infection and how the virus plays a role in manipulating certain regulatory mechanisms to make these cells dysfunctional for its own persistence and survival.
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Affiliation(s)
- Shallu Tomer
- Department of Immunopathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
| | - Sunil K Arora
- Department of Immunopathology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
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22
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Sonon P, Collares CVA, Ferreira MLB, Almeida RS, Sadissou I, Cordeiro MT, de Fátima Militão de Albuquerque M, Castelli EC, Lucena-Silva N, Donadi EA. Peripheral spectrum neurological disorder after arbovirus infection is associated with HLA-F variants among Northeastern Brazilians. INFECTION GENETICS AND EVOLUTION 2021; 92:104855. [PMID: 33839310 DOI: 10.1016/j.meegid.2021.104855] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 04/02/2021] [Accepted: 04/06/2021] [Indexed: 01/02/2023]
Abstract
INTRODUCTION Non-classical class I human leukocyte antigens (HLA) molecules are known to modulate the function of cytotoxic cells (NK and T CD8+) during viral infection by interacting with inhibitory/activating receptors. However, little is known about the HLA-E/-F genetic variability on arbovirus infections. METHODS We evaluated by massive parallel sequencing the full HLA-E/-F genetic diversity among patients infected during the arbovirus (ZIKV, DENV, and CHIKV) outbreak leading to a broad range of neurological complications in the Brazilian State of Pernambuco. In parallel, healthy blood donors from the same area were also studied. Plink and R software were used for genetic association study. To limit the false-positive results and enhance the reliability of the results, we adopted P-values <0.01 as significant levels. RESULTS Compared to controls, the HLA-F alleles: -1610 C (rs17875375), +1383 G (rs17178385), and +3537 A (rs17875384), all in complete linkage disequilibrium with each other (r2 = 1), were overrepresented in patients presenting peripheral spectrum disorders (PSD). The HLA-F*Distal-D haplotype that harbored the -1610 C allele exhibited a trend increase in PSD group. No associations were found for HLA-E. CONCLUSIONS Our findings showed that the HLA-F genetic background seems to be more important than HLA-E on the susceptibility to PSD complications.
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Affiliation(s)
- Paulin Sonon
- Immunogenetic Laboratory, Immunology Department, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Moraes rego, s/n, Campus da UFPE, Cidade Universitária, 50670420 Recife, PE, Brazil; Ribeirão Preto Medical School, University of São Paulo, AV Bandeirantes, 3900, HC, Vila Monte Alegre, 14049900 Ribeirão Preto, SP, Brazil
| | - Cristhianna V A Collares
- Ribeirão Preto Medical School, University of São Paulo, AV Bandeirantes, 3900, HC, Vila Monte Alegre, 14049900 Ribeirão Preto, SP, Brazil
| | - Maria Lúcia Brito Ferreira
- Hospital da Restauração Gov. Paulo Guerra, Av. Gov. Agamenon Magalhães, s/n, Derby, 52171011 Recife, PE, Brazil
| | - Renata Santos Almeida
- Immunogenetic Laboratory, Immunology Department, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Moraes rego, s/n, Campus da UFPE, Cidade Universitária, 50670420 Recife, PE, Brazil
| | - Ibrahim Sadissou
- Ribeirão Preto Medical School, University of São Paulo, AV Bandeirantes, 3900, HC, Vila Monte Alegre, 14049900 Ribeirão Preto, SP, Brazil
| | - Marli Tenório Cordeiro
- Virology Department, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Moraes rego, s/n, Campus da UFPE, Cidade Universitária, 50670420 Recife, PE, Brazil
| | - Maria de Fátima Militão de Albuquerque
- Public Health Department, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Moraes rego, s/n, Campus da UFPE, Cidade Universitária, 50670420 Recife, PE, Brazil
| | - Erick C Castelli
- São Paulo State University (UNESP), School of Medicine, Molecular Genetics and Bioinformatics Laboratory, Prof. Dr. Walter Maurício Correa, s/n Unesp, Campus de Botucatu, Botucatu CEP 18618681, SP, Brazil; São Paulo State University (UNESP), Department of Pathology, School of Medicine, Botucatu, SP, Brazil
| | - Norma Lucena-Silva
- Immunogenetic Laboratory, Immunology Department, Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Av. Moraes rego, s/n, Campus da UFPE, Cidade Universitária, 50670420 Recife, PE, Brazil
| | - Eduardo A Donadi
- Ribeirão Preto Medical School, University of São Paulo, AV Bandeirantes, 3900, HC, Vila Monte Alegre, 14049900 Ribeirão Preto, SP, Brazil.
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23
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Sun H, Wu Y, Zhang Y, Ni B. IL-10-Producing ILCs: Molecular Mechanisms and Disease Relevance. Front Immunol 2021; 12:650200. [PMID: 33859642 PMCID: PMC8042445 DOI: 10.3389/fimmu.2021.650200] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 03/11/2021] [Indexed: 12/19/2022] Open
Abstract
Innate lymphoid cells (ILCs) are mainly composed of natural killer (NK) cells and helper-like lymphoid cells, which play a vital role in maintaining tissue homeostasis, enhancing adaptive immunity and regulating tissue inflammation. Alteration of the distribution and function of ILCs subgroups are closely related to the pathogenesis of inflammatory diseases and cancers. Interleukin-10 (IL-10) is a highly pleiotropic cytokine, and can be secreted by several cell types, among of which ILCs are recently verified to be a key source of IL-10. So far, the stable production of IL-10 can only be observed in certain NK subsets and ILC2s. Though the regulatory mechanisms for ILCs to produce IL-10 are pivotal for understanding ILCs and potential intervenes of diseases, which however is largely unknown yet. The published studies show that ILCs do not share exactly the same mechanisms for IL-10 production with helper T cells. In this review, the molecular mechanisms regulating IL-10 production in NK cells and ILC2s are discussed in details for the first time, and the role of IL-10-producing ILCs in diseases such as infections, allergies, and cancers are summarized.
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Affiliation(s)
- Hui Sun
- Department of Pathophysiology, Third Military Medical University, Chongqing, China
| | - Yuzhang Wu
- Chongqing International Institute for Immunology, Chongqing, China
| | - Yi Zhang
- Chongqing International Institute for Immunology, Chongqing, China
| | - Bing Ni
- Department of Pathophysiology, Third Military Medical University, Chongqing, China
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24
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Nan FL, Zheng W, Nan WL, Yu T, Xie CZ, Zhang H, Xu XH, Li CH, Ha Z, Zhang JY, Zhuang XY, Han JC, Wang W, Qian J, Zhao GY, Li ZX, Ge JY, Bu ZG, Zhang Y, Lu HJ, Jin NY. Newcastle Disease Virus Inhibits the Proliferation of T Cells Induced by Dendritic Cells In Vitro and In Vivo. Front Immunol 2021; 11:619829. [PMID: 33708193 PMCID: PMC7942023 DOI: 10.3389/fimmu.2020.619829] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/29/2020] [Indexed: 12/03/2022] Open
Abstract
Newcastle disease virus (NDV) infects poultry and antagonizes host immunity via several mechanisms. Dendritic cells (DCs) are characterized as specialized antigen presenting cells, bridging innate and adaptive immunity and regulating host resistance to viral invasion. However, there is little specific knowledge of the role of DCs in NDV infection. In this study, the representative NDV lentogenic strain LaSota was used to explore whether murine bone marrow derived DCs mature following infection. We examined surface molecule expression and cytokine release from DCs as well as proliferation and activation of T cells in vivo and in vitro in the context of NDV. The results demonstrated that infection with lentogenic strain LaSota induced a phenotypic maturation of immature DCs (imDCs), which actually led to curtailed T cell responses. Upon infection, the phenotypic maturation of DCs was reflected by markedly enhanced MHC and costimulatory molecule expression and secretion of proinflammatory cytokines. Nevertheless, NDV-infected DCs produced the anti-inflammatory cytokine IL-10 and attenuated T cell proliferation, inducing Th2-biased responses. Therefore, our study reveals a novel understanding that DCs are phenotypically mature but dysfunctional in priming T cell responses during NDV infection.
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Affiliation(s)
- Fu Long Nan
- College of Veterinary Medicine, College of Animal Science, Jilin University, Changchun, China.,Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
| | - Wei Zheng
- The 964Hospital of the PLA Joint Logistics, Changchun, China
| | - Wen Long Nan
- China Animal Health and Epidemiology Center, Qingdao, China
| | - Tong Yu
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China.,Agricultural College, Yanbian University, Yanji, China
| | - Chang Zhan Xie
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
| | - He Zhang
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
| | - Xiao Hong Xu
- College of Veterinary Medicine, College of Animal Science, Jilin University, Changchun, China
| | - Cheng Hui Li
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
| | - Zhuo Ha
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
| | - Jin Yong Zhang
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
| | - Xin Yu Zhuang
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
| | - Ji Cheng Han
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China.,Academician Workstation, Changchun University of Chinese Medicine, Changchun, China
| | - Wei Wang
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
| | - Jing Qian
- Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Nanjing, China
| | - Guan Yu Zhao
- College of Veterinary Medicine, College of Animal Science, Jilin University, Changchun, China.,Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
| | - Zhuo Xin Li
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
| | - Jin Ying Ge
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Zhi Gao Bu
- State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
| | - Ying Zhang
- College of Veterinary Medicine, College of Animal Science, Jilin University, Changchun, China
| | - Hui Jun Lu
- Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
| | - Ning Yi Jin
- College of Veterinary Medicine, College of Animal Science, Jilin University, Changchun, China.,Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Changchun, China
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25
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Zwirner NW, Domaica CI, Fuertes MB. Regulatory functions of NK cells during infections and cancer. J Leukoc Biol 2020; 109:185-194. [PMID: 33095941 DOI: 10.1002/jlb.3mr0820-685r] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 08/16/2020] [Accepted: 09/24/2020] [Indexed: 01/02/2023] Open
Abstract
After recognition, NK cells can kill susceptible target cells through perforin-dependent mechanisms or by inducing death receptor-mediated apoptosis, and they can also secrete cytokines that are pivotal for immunomodulation. Despite the critical role as effector cells against tumors and virus-infected cells, NK cells have been implicated in the regulation of T cell-mediated responses in different models of autoimmunity, transplantation, and viral infections. Here, we review the mechanisms described for NK cell-mediated inhibition of adaptive immune responses, with spotlight on the emerging evidence of their regulatory role that shapes antitumor immune responses.
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Affiliation(s)
- Norberto W Zwirner
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.,Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Carolina I Domaica
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Mercedes B Fuertes
- Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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26
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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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Burwitz BJ, Hashiguchi PK, Mansouri M, Meyer C, Gilbride RM, Biswas S, Womack JL, Reed JS, Wu HL, Axthelm MK, Hansen SG, Picker LJ, Früh K, Sacha JB. MHC-E-Restricted CD8 + T Cells Target Hepatitis B Virus-Infected Human Hepatocytes. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 204:2169-2176. [PMID: 32161099 PMCID: PMC8109620 DOI: 10.4049/jimmunol.1900795] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 02/05/2020] [Indexed: 12/30/2022]
Abstract
Currently 247 million people are living with chronic hepatitis B virus infection (CHB), and the development of novel curative treatments is urgently needed. Immunotherapy is an attractive approach to treat CHB, yet therapeutic approaches to augment the endogenous hepatitis B virus (HBV)-specific T cell response in CHB patients have demonstrated little success. In this study, we show that strain 68-1 rhesus macaque (RM) CMV vaccine vectors expressing HBV Ags engender HBV-specific CD8+ T cells unconventionally restricted by MHC class II and the nonclassical MHC-E molecule in RM. Surface staining of human donor and RM primary hepatocytes (PH) ex vivo revealed the majority of PH expressed MHC-E but not MHC class II. HBV-specific, MHC-E-restricted CD8+ T cells from RM vaccinated with RM CMV vaccine vectors expressing HBV Ags recognized HBV-infected PH from both human donor and RM. These results provide proof-of-concept that MHC-E-restricted CD8+ T cells could be harnessed for the treatment of CHB, either through therapeutic vaccination or adoptive immunotherapy.
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Affiliation(s)
- Benjamin J Burwitz
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
| | - Patrick K Hashiguchi
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Mandana Mansouri
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | | | - Roxanne M Gilbride
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Sreya Biswas
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Jennie L Womack
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Jason S Reed
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Helen L Wu
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Michael K Axthelm
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
| | - Scott G Hansen
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
| | - Louis J Picker
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
| | - Klaus Früh
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006;
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
| | - Jonah B Sacha
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006;
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
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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: 17] [Impact Index Per Article: 3.4] [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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Abulizi A, Shao Y, Aji T, Li Z, Zhang C, Aini A, Wang H, Tuxun T, Li L, Zhang N, Lin R, Wen H. Echinococcus multilocularis inoculation induces NK cell functional decrease through high expression of NKG2A in C57BL/6 mice. BMC Infect Dis 2019; 19:792. [PMID: 31500589 PMCID: PMC6734356 DOI: 10.1186/s12879-019-4417-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 08/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alveolar echinococcosis (AE) is caused by the larval stage of Echinococcus multilocularis (E. multilocularis), and considered as public health issue. Parasite-host immune interaction is pivotal during infection. As a subset of innate lymphoid cells, NK cells are known to play an important role during virus, bacteria, intra/extracellular parasitic infections and tumor progression. However, the possible role of NK cells in E. multilocularis infection in both human and murine is little known. Herein, the functional alteration of hepatic NK cells and their related molecules in E. multilocularis infected mice were studied. METHODS 2000 protoscoleces (PSCs) were injected to C57BL/6 mice via the portal vein to establish secondary E. multilocularis infection. NK cells population and their related molecules (CD69, Ly49D, Ly49G2, Ly49H, Ly49I, NKG2A, NKG2D, granzyme B, IFN-γ, TNF-α) were assessed by using fluorescence-activated cell sorter (FACS) techniques and qRT-PCR. NK cell depletion was performed for further understanding the possible function of NK cells during infection. RESULTS The total frequencies of NK cells and NK-derived IFN-γ production were significantly reduced at designated time points (2, 4, 12 weeks). The liver resident (CD49a+DX5-) NK cells are decreased at 4 weeks after inoculation and which is significantly lower than in control mice. Moreover, in vivo antibody-mediated NK cell depletion increased parasitic load and decreased peri-parasitic fibrosis. Expression of the inhibitory receptor NKG2A was negatively related to NK- derived IFN-γ secretion. CONCLUSIONS Our study showed down regulates of NK cells and upper regulates of NKG2A expression on NK cells during E. multilocularis infection. Reduction of NK cell frequencies and increased NKG2A might result in low cytotoxic activity through decreased IFN-γ secretion in E. multilocularis infection. This result might be helpful to restore NK cell related immunity against E. multilocularis infection to treat alveolar echinococcosis.
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Affiliation(s)
- Abuduaini Abulizi
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Hepatobiliary & Hydatid Disease Department, Digestive & Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
| | - Yingmei Shao
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Hepatobiliary & Hydatid Disease Department, Digestive & Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
- WHO Collaborating Center on Prevention and Management of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
| | - Tuerganaili Aji
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Hepatobiliary & Hydatid Disease Department, Digestive & Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
- WHO Collaborating Center on Prevention and Management of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
| | - Zhide Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Hepatobiliary & Hydatid Disease Department, Digestive & Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
| | - Chuanshan Zhang
- WHO Collaborating Center on Prevention and Management of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
- Xinjiang Key Laboratory of Fundamental Research on Echinococcosis, Clinical Medical Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
| | - Abudusalamu Aini
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Hepatobiliary & Hydatid Disease Department, Digestive & Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
| | - Hui Wang
- WHO Collaborating Center on Prevention and Management of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
- Xinjiang Key Laboratory of Fundamental Research on Echinococcosis, Clinical Medical Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
| | - Tuerhongjiang Tuxun
- Department of Liver and Laparoscopic Surgery, Digestive & Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
| | - Liang Li
- WHO Collaborating Center on Prevention and Management of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
- Xinjiang Key Laboratory of Fundamental Research on Echinococcosis, Clinical Medical Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
| | - Ning Zhang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Hepatobiliary & Hydatid Disease Department, Digestive & Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
| | - Renyong Lin
- WHO Collaborating Center on Prevention and Management of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
- Xinjiang Key Laboratory of Fundamental Research on Echinococcosis, Clinical Medical Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
| | - Hao Wen
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Hepatobiliary & Hydatid Disease Department, Digestive & Vascular Surgery Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
- WHO Collaborating Center on Prevention and Management of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
- Xinjiang Key Laboratory of Fundamental Research on Echinococcosis, Clinical Medical Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054 China
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Poznanski SM, Ashkar AA. What Defines NK Cell Functional Fate: Phenotype or Metabolism? Front Immunol 2019; 10:1414. [PMID: 31275330 PMCID: PMC6593107 DOI: 10.3389/fimmu.2019.01414] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Accepted: 06/04/2019] [Indexed: 01/03/2023] Open
Abstract
NK cells are capable of an array of functions that range widely from their classic anti-tumor and anti-viral cytotoxic effector functions, to their critical regulatory roles in controlling inflammatory immune responses and promoting tissue growth. However, the mechanisms that polarize NK cells to these distinct and opposing functions are incompletely understood. NK cell functional subsets are primarily identified and studied based on phenotype, which has served as an accessible means for profiling NK cells and does offer information on NK cell activation state. However, inconsistencies have emerged in using classic phenotypes to inform function, which raise the questions: Can phenotype in fact define NK cell functional fate? What factors do profile and drive NK cell fate? In other immune cells, cell metabolism has been shown to critically determine subset polarization. There is a growing body of evidence that cell metabolism is integral to NK cell effector functions. Glucose-driven glycolysis and oxidative metabolism have been shown to drive classic NK cell anti-tumor and anti-viral effector functions. Recent studies have uncovered a critical role for metabolism in NK cell development, education, and memory generation. In this review, we will draw on the evidence to date to investigate the relationship between NK cell phenotype, metabolism, and functional fate. We explore a paradigm in which the differential activity of metabolic pathways within NK cells produce distinct metabolic fingerprints that comprehensively distinguish and drive the range of NK cell functional abilities. We will discuss future areas of study that are needed to develop and test this paradigm and suggest strategies to efficiently profile NK cells based on metabolism. Given the emerging role of metabolism in driving NK cell fates, profiling and modulating NK cell metabolism holds profound therapeutic potential to tune inflammatory and regulatory NK cell responses to treat disease.
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Affiliation(s)
- Sophie M Poznanski
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
| | - Ali A Ashkar
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON, Canada
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31
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Humanized Mouse Models for the Study of Hepatitis C and Host Interactions. Cells 2019; 8:cells8060604. [PMID: 31213010 PMCID: PMC6627916 DOI: 10.3390/cells8060604] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 06/09/2019] [Accepted: 06/13/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection is commonly attributed as a major cause of chronic hepatotropic diseases, such as, steatosis, cirrhosis and hepatocellular carcinoma. As HCV infects only humans and primates, its narrow host tropism hampers in vivo studies of HCV-mammalian host interactions and the development of effective therapeutics and vaccines. In this context, we will focus our discussion on humanized mice in HCV research. Here, these humanized mice are defined as animal models that encompass either only human hepatocytes or both human liver and immune cells. Aspects related to immunopathogenesis, anti-viral interventions, drug testing and perspectives of these models for future HCV research will be discussed.
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32
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Stevenson TJ, Barbour Y, McMahon BJ, Townshend-Bulson L, Hewitt AM, Espera HGF, Homan C, Holck P, Luna SV, Knall C, Simons BC. Observed Changes in Natural Killer and T cell Phenotypes with Evaluation of Immune Outcome in a Longitudinal Cohort Following Sofosbuvir-Based Therapy for Chronic Hepatitis C Infection. Open Forum Infect Dis 2019; 6:ofz223. [PMID: 31249845 PMCID: PMC6589029 DOI: 10.1093/ofid/ofz223] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 05/10/2019] [Indexed: 12/12/2022] Open
Abstract
Background Chronic hepatitis C virus (HCV) infection diminishes immune function through cell exhaustion and repertoire alteration. Direct acting antiviral (DAA)-based therapy can restore immune cell subset function and reduce exhaustion states. However, the extent of immune modulation following DAA-based therapy and the role that clinical and demographic factors play remain unknown. Methods We examined natural killer (NK) cell, CD4+, and CD8+ T cell subsets along with activation and exhaustion phenotypes across an observational study of sofosbuvir-based treatment for chronic HCV infection. Additionally, we examined the ability of clinical variables and duration of infection to predict 12 weeks of sustained virologic response (SVR12) immune marker outcomes. Results We show that sofosbuvir-based therapy restores NK cell subset distributions and reduces chronic activation by SVR12. Likewise, T cell subsets, including HCV-specific CD8+ T cells, show reductions in chronic exhaustion markers by SVR12. Immunosuppressive CD4+ regulatory T cells decrease at 4-weeks treatment and SVR12. We observe the magnitude and direction of change in immune marker values from pretreatment to SVR12 varies greatly among participants. Although we observed associations between the estimated date of infection, HCV diagnosis date, and extent of immune marker outcome at SVR12, our regression analyses did not indicate any factors as strong SVR12 outcome predictors. Conclusion Our study lends further evidence of immune changes following sofosbuvir-based therapy. Further investigation beyond SVR12 and into factors that may predict posttreatment outcome is warranted.
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Affiliation(s)
- Timothy J Stevenson
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Youssef Barbour
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Brian J McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Lisa Townshend-Bulson
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Annette M Hewitt
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Hannah G F Espera
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Chriss Homan
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Peter Holck
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Sarah V Luna
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage
| | - Cindy Knall
- WWAMI (Washington, Wyoming, Alaska, Montana, and Idaho) School of Medical Education, University of Alaska, Anchorage
| | - Brenna C Simons
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage.,WWAMI (Washington, Wyoming, Alaska, Montana, and Idaho) School of Medical Education, University of Alaska, Anchorage
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33
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Mikulak J, Bruni E, Oriolo F, Di Vito C, Mavilio D. Hepatic Natural Killer Cells: Organ-Specific Sentinels of Liver Immune Homeostasis and Physiopathology. Front Immunol 2019; 10:946. [PMID: 31114585 PMCID: PMC6502999 DOI: 10.3389/fimmu.2019.00946] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 04/12/2019] [Indexed: 12/16/2022] Open
Abstract
The liver is considered a preferential tissue for NK cells residency. In humans, almost 50% of all intrahepatic lymphocytes are NK cells that are strongly imprinted in a liver-specific manner and show a broad spectrum of cellular heterogeneity. Hepatic NK (he-NK) cells play key roles in tuning liver immune response in both physiological and pathological conditions. Therefore, there is a pressing need to comprehensively characterize human he-NK cells to better understand the related mechanisms regulating their effector-functions within the dynamic balance between immune-tolerance and immune-surveillance. This is of particular relevance in the liver that is the only solid organ whose parenchyma is constantly challenged on daily basis by millions of foreign antigens drained from the gut. Therefore, the present review summarizes our current knowledge on he-NK cells in the light of the latest discoveries in the field of NK cell biology and clinical relevance.
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Affiliation(s)
- Joanna Mikulak
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Elena Bruni
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Ferdinando Oriolo
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Clara Di Vito
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
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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: 101] [Impact Index Per Article: 16.8] [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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36
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Sung PS, Jang JW. Natural Killer Cell Dysfunction in Hepatocellular Carcinoma: Pathogenesis and Clinical Implications. Int J Mol Sci 2018; 19:3648. [PMID: 30463262 PMCID: PMC6274919 DOI: 10.3390/ijms19113648] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/16/2018] [Accepted: 11/16/2018] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is currently the third leading cause of malignancy-related mortalities worldwide. Natural killer (NK) cells are involved in the critical role of first line immunological defense against cancer development. Defects in NK cell functions are recognized as important mechanisms for immune evasion of tumor cells. NK cell function appears to be attenuated in HCC, and many previous reports suggested that NK cells play a critical role in controlling HCC, suggesting that boosting the activity of dysfunctional NK cells can enhance tumor cell killing. However, the detailed mechanisms of NK cell dysfunction in tumor microenvironment of HCC remain largely unknown. A better understanding of the mechanisms of NK cell dysfunction in HCC will help in the NK cell-mediated eradication of cancer cells and prolong patient survival. In this review, we describe the various mechanisms underlying human NK cell dysfunction in HCC. Further, we summarize current advances in the approaches to enhance endogenous NK cell function and in adoptive NK cell therapies, to cure this difficult-to-treat cancer.
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Affiliation(s)
- Pil Soo Sung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
| | - Jeong Won Jang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
- The Catholic Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.
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Suda T, Tatsumi T, Nishio A, Kegasawa T, Yoshioka T, Yamada R, Furuta K, Kodama T, Shigekawa M, Hikita H, Sakamori R, Fukuhara T, Matsuura Y, Takehara T. CEACAM1 Is Associated With the Suppression of Natural Killer Cell Function in Patients With Chronic Hepatitis C. Hepatol Commun 2018; 2:1247-1258. [PMID: 30288478 PMCID: PMC6167072 DOI: 10.1002/hep4.1240] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 05/20/2018] [Indexed: 12/15/2022] Open
Abstract
Natural killer cells (NK cells) play an essential role in the immunological mechanism underlying chronic hepatitis C (CHC). Impairment of NK cell function facilitates persistent infection with hepatitis C virus (HCV) and hepatocellular carcinogenesis. However, the mechanism by which NK cell activity is suppressed in CHC is not completely understood. In this study, we focused on carcinoembryonic antigen–related cell‐adhesion molecule 1 (CEACAM1). CEACAM1 is thought to suppress NK cell function. We examined the effect of CEACAM1 on NK cell function in CHC. We investigated the function of CEACAM1 in vitro using Huh7.5.1 cells and the HCV‐Japanese fulminant hepatitis (JFH)‐1 strain. We analyzed serum CEACAM1 level, NK cell function, and CEACAM1 messenger RNA (mRNA) level in human liver samples. Levels of CEACAM1 on the cell surface, CEACAM1 mRNA levels, and soluble CEACAM1 levels in supernatants were significantly higher in Huh7.5.1 cells infected with JFH‐1 (Huh7.5.1/JFH‐1 cells) than in Huh7.5.1 cells. Significantly higher NK cell cytotoxicity was observed toward K562 cells after coculture with CEACAM1 knockout Huh7.5.1/JFH‐1 cells than after coculture with Huh7.5.1/JFH‐1 cells. CEACAM1 expression was induced by the HCV E2 glycoprotein in HCV infection. Significantly higher serum CEACAM1 levels were detected in patients with CHC compared with healthy subjects and patients who achieved sustained virological responses. The expression of CD107a on NK cells from patients with CHC was negatively correlated with serum CEACAM1 levels. Significantly higher levels of CEACAM1 mRNA were detected in HCV‐infected livers compared with uninfected livers. Conclusion: CEACAM1 expression was induced in hepatocytes following HCV infection and decreased NK cell cytotoxicity. These results demonstrate a possible role for CEACAM1 in the pathogenesis of CHC and hepatocellular carcinoma progression.
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Affiliation(s)
- Takahiro Suda
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Akira Nishio
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Tadashi Kegasawa
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Teppei Yoshioka
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Ryoko Yamada
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Kunimaro Furuta
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Takahiro Kodama
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Minoru Shigekawa
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
| | - Takasuke Fukuhara
- Department of Molecular Virology Research Institute for Microbial Diseases, Osaka University Suita Japan
| | - Yoshiharu Matsuura
- Department of Molecular Virology Research Institute for Microbial Diseases, Osaka University Suita Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology Osaka University Graduate School of Medicine Suita Japan
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Cytokine-Modulated Natural Killer Cells Differentially Regulate the Activity of the Hepatitis C Virus. Int J Mol Sci 2018; 19:ijms19092771. [PMID: 30223493 PMCID: PMC6163477 DOI: 10.3390/ijms19092771] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 09/13/2018] [Accepted: 09/13/2018] [Indexed: 01/09/2023] Open
Abstract
HCV genotype 2a strain JFH-1 replicates and produces viral particles efficiently in human hepatocellular carcinoma (huh) 7.5 cells, which provide a stable in vitro cell infection system for the hepatitis C virus (HCVcc system). Natural killer (NK) cells are large lymphoid cells that recognize and kill virus-infected cells. In this study, we investigated the interaction between NK cells and the HCVcc system. IL-10 is a typical immune regulatory cytokine that is produced mostly by NK cells and macrophages. IL-21 is one of the main cytokines that stimulate the activation of NK cells. First, we used anti-IL-10 to neutralize IL-10 in a coculture of NK cells and HCVcc. Anti-IL-10 treatment increased the maturation of NK cells by enhancing the frequency of the CD56+dim population in NK-92 cells. However, with anti-IL-10 treatment of NK cells in coculture with J6/JFH-1-huh 7.5 cells, there was a significant decrease in the expression of STAT1 and STAT5 proteins in NK-92 cells and an increase in the HCV Core and NS3 proteins. In addition, rIL-21 treatment increased the frequency of the CD56+dim population in NK-92 cells, Also, there was a dramatic increase in the expression of STAT1 and STAT5 proteins in rIL-21 pre-stimulated NK cells and a decrease in the expression of HCV Core protein in coculture with J6/JFH-1-huh 7.5 cells. In summary, we found that the functional activation of NK cells can be modulated by anti-IL-10 or rIL-21, which controls the expression of HCV proteins as well as HCV RNA replication.
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Dansako H, Imai H, Ueda Y, Satoh S, Wakita T, Kato N. ULBP1 is induced by hepatitis C virus infection and is the target of the NK cell-mediated innate immune response in human hepatocytes. FEBS Open Bio 2018; 8:361-371. [PMID: 29511613 PMCID: PMC5832972 DOI: 10.1002/2211-5463.12373] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 12/04/2017] [Accepted: 12/18/2017] [Indexed: 01/25/2023] Open
Abstract
Natural killer (NK) cells through their NK group 2 member D (NKG2D) receptors recognize NKG2D ligands such as UL16‐binding proteins (ULBPs) on virus‐infected cells and subsequently trigger the host innate immune response. In the present study, we demonstrated that hepatitis C virus (HCV) induced the cell surface expression of ULBP1 in human immortalized hepatocyte PH5CH8 cells and human hepatoma HuH‐7 cell‐derived RSc cells. Interestingly, NK cell line NK‐92 induced cytotoxicity and interferon‐γ mRNA expression and subsequently reduced the levels of HCV RNA replication during co‐culture with HCV‐infected RSc cells. From these results, we conclude that ULBP1 is a target of the NK cell‐mediated innate immune response in HCV‐infected human hepatocytes.
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Affiliation(s)
- Hiromichi Dansako
- Department of Tumor Virology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan
| | - Hirotaka Imai
- Department of Tumor Virology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan
| | - Youki Ueda
- Department of Tumor Virology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan
| | - Shinya Satoh
- Department of Tumor Virology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan
| | - Takaji Wakita
- Department of Virology II National Institute of Infectious Disease Tokyo Japan
| | - Nobuyuki Kato
- Department of Tumor Virology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences Okayama Japan
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40
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Wu Y, Tian Z, Wei H. Developmental and Functional Control of Natural Killer Cells by Cytokines. Front Immunol 2017; 8:930. [PMID: 28824650 PMCID: PMC5543290 DOI: 10.3389/fimmu.2017.00930] [Citation(s) in RCA: 202] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 07/20/2017] [Indexed: 12/20/2022] Open
Abstract
Natural killer (NK) cells are effective in combating infections and tumors and as such are tempting for adoptive transfer therapy. However, they are not homogeneous but can be divided into three main subsets, including cytotoxic, tolerant, and regulatory NK cells, with disparate phenotypes and functions in diverse tissues. The development and functions of such NK cells are controlled by various cytokines, such as fms-like tyrosine kinase 3 ligand (FL), kit ligand (KL), interleukin (IL)-3, IL-10, IL-12, IL-18, transforming growth factor-β, and common-γ chain family cytokines, which operate at different stages by regulating distinct signaling pathways. Nevertheless, the specific roles of each cytokine that regulates NK cell development or that shapes different NK cell functions remain unclear. In this review, we attempt to describe the characteristics of each cytokine and the existing protocols to expand NK cells using different combinations of cytokines and feeder cells. A comprehensive understanding of the role of cytokines in NK cell development and function will aid the generation of better efficacy for adoptive NK cell treatment.
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Affiliation(s)
- Yang Wu
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China
| | - Zhigang Tian
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China
| | - Haiming Wei
- Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science and Technology of China, Hefei, China.,Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, Hefei, China
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41
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Crux NB, Elahi S. Human Leukocyte Antigen (HLA) and Immune Regulation: How Do Classical and Non-Classical HLA Alleles Modulate Immune Response to Human Immunodeficiency Virus and Hepatitis C Virus Infections? Front Immunol 2017; 8:832. [PMID: 28769934 PMCID: PMC5513977 DOI: 10.3389/fimmu.2017.00832] [Citation(s) in RCA: 141] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 06/30/2017] [Indexed: 12/13/2022] Open
Abstract
The genetic factors associated with susceptibility or resistance to viral infections are likely to involve a sophisticated array of immune response. These genetic elements may modulate other biological factors that account for significant influence on the gene expression and/or protein function in the host. Among them, the role of the major histocompatibility complex in viral pathogenesis in particular human immunodeficiency virus (HIV) and hepatitis C virus (HCV), is very well documented. We, recently, added a novel insight into the field by identifying the molecular mechanism associated with the protective role of human leukocyte antigen (HLA)-B27/B57 CD8+ T cells in the context of HIV-1 infection and why these alleles act as a double-edged sword protecting against viral infections but predisposing the host to autoimmune diseases. The focus of this review will be reexamining the role of classical and non-classical HLA alleles, including class Ia (HLA-A, -B, -C), class Ib (HLA-E, -F, -G, -H), and class II (HLA-DR, -DQ, -DM, and -DP) in immune regulation and viral pathogenesis (e.g., HIV and HCV). To our knowledge, this is the very first review of its kind to comprehensively analyze the role of these molecules in immune regulation associated with chronic viral infections.
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Affiliation(s)
- Nicole B. Crux
- Faculty of Medicine and Dentistry, Department of Dentistry, University of Alberta, Edmonton, AB, Canada
- Faculty of Medicine and Dentistry, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
| | - Shokrollah Elahi
- Faculty of Medicine and Dentistry, Department of Dentistry, University of Alberta, Edmonton, AB, Canada
- Faculty of Medicine and Dentistry, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB, Canada
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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: 10] [Impact Index Per Article: 1.3] [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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43
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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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Yoshioka T, Tatsumi T, Miyagi T, Mukai K, Nishio K, Nishio A, Yokoyama Y, Suda T, Kegasawa T, Shigekawa M, Hikita H, Sakamori R, Takehara T. Frequency and role of NKp46 and NKG2A in hepatitis B virus infection. PLoS One 2017; 12:e0174103. [PMID: 28328926 PMCID: PMC5362099 DOI: 10.1371/journal.pone.0174103] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 03/04/2017] [Indexed: 12/20/2022] Open
Abstract
Background and Aim Natural Killer (NK) cells are involved in the control of viral infection. However, the role of NK cells in chronic hepatitis B (CHB) remains unclear. This study investigated the frequencies and roles of NK cells in CHB, with a focus on activating receptor NKp46 and inhibitory receptor NKG2A. Patients/Method Peripheral blood lymphocytes were obtained from 71 CHB patients and 37 healthy subjects (HS). The expressions of NKp46 and NKG2A were analyzed using flow cytometry. The role of NKp46-ligand was assessed using an in vitro co-culture system. Cytotoxicity and IFN-γ production in NK cells were evaluated using RT-PCR and flow cytometry. Results CHB patients were classified into treatment-naïve patients with low HBV DNA titer (CHB-L; n = 28), high HBV DNA titer (CHB-H; n = 24) by the cut-off level of serum HBV DNA 4 log copies/ml, and patients receiving nucleos(t)ide analogue (CHB-NA; n = 19). The expressions of NKp46 and NKG2A were higher in CHB-H than in HS/CHB-L/CHB-NA. HepG2.2.15 had higher NKp46-ligand expression than HepG2. When NK cells from HS were co-cultured with HepG2.2.15, inhibition of the NKp46 and NKp46-ligand interaction by anti-NKp46 antibody significantly reduced cytolysis of HepG2.2.15 and IFN-γ production. However, those reductions were not observed in co-culture with HepG2. Additionally, NK cells that highly expressed NKp46 also highly expressed NKG2A (NKp46highNKG2Ahigh subset). The frequencies of NKp46highNKG2Ahigh subset in CHB-H were higher than those in HS/CHB-L/CHB-NA. Among treatment-naïve CHB patients, the frequencies of NKp46highNKG2Ahigh subset were positively correlated with serum ALT (P<0.01, r = 0.45) and HBV DNA (P<0.01, r = 0.59) levels. The expressions of Fas-L, STAT1, TRAIL and CD107a were higher and IFN-γ expression was lower in the NKp46highNKG2Ahigh subset than in the other subsets. Conclusion The NKp46 and NKp46-ligand interaction contributes to NK cell activation. A novel NK cell subset, the NKp46highNKG2Ahigh subset, may be associated with liver injury and HBV replication.
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Affiliation(s)
- Teppei Yoshioka
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tomohide Tatsumi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takuya Miyagi
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kaori Mukai
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Kumiko Nishio
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Akira Nishio
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Yoshinobu Yokoyama
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Takahiro Suda
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tadashi Kegasawa
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Minoru Shigekawa
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Hayato Hikita
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Ryotaro Sakamori
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
| | - Tetsuo Takehara
- Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
- * E-mail:
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45
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Brown DL. Immunopathology of the Hepatobiliary System. MOLECULAR AND INTEGRATIVE TOXICOLOGY 2017:329-417. [DOI: 10.1007/978-3-319-47385-7_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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46
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NK-DC Crosstalk in Immunity to Microbial Infection. J Immunol Res 2016; 2016:6374379. [PMID: 28097157 PMCID: PMC5206438 DOI: 10.1155/2016/6374379] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 11/13/2016] [Indexed: 12/11/2022] Open
Abstract
The interaction between natural killer (NK) cell and dendritic cell (DC), two important cellular components of innate immunity, started to be elucidated in the last years. The crosstalk between NK cells and DC, which leads to NK cell activation, DC maturation, or apoptosis, involves cell-cell contacts and soluble factors. This interaction either in the periphery or in the secondary lymphoid organs acts as a key player linking innate and adaptive immune responses to microbial stimuli. This review focuses on the mechanisms of NK-DC interaction and their relevance in antimicrobial responses. We specifically aim to emphasize the ability of various microbial infections to differently influence NK-DC crosstalk thereby contributing to distinct adaptive immune response.
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47
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Sun C, Xu J, Huang Q, Huang M, Wen H, Zhang C, Wang J, Song J, Zheng M, Sun H, Wei H, Xiao W, Sun R, Tian Z. High NKG2A expression contributes to NK cell exhaustion and predicts a poor prognosis of patients with liver cancer. Oncoimmunology 2016; 6:e1264562. [PMID: 28197391 DOI: 10.1080/2162402x.2016.1264562] [Citation(s) in RCA: 205] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 11/15/2016] [Accepted: 11/17/2016] [Indexed: 02/08/2023] Open
Abstract
Background and Aims: As the predominant lymphocyte subset in the liver, natural killer (NK) cells have been shown to be highly associated with the outcomes of patients with chronic hepatitis B virus infection (CHB) and hepatocellular carcinoma (HCC). Previously, we reported that NKG2A, a checkpoint candidate, mediates human and murine NK cell dysfunction in CHB. However, NK cell exhaustion and, particularly, the level of NKG2A expression within liver tumors have not been reported. Methods: In this study, we analyzed NKG2A expression and the related dysfunction of NK cells located in intra- or peritumor regions of liver tissue samples from 207 HCC patients, in addition to analyzing disease outcomes. Results: The expression of NKG2A in NK cells and the NKG2A ligand, HLA-E, in intratumor HCC tissues was observed to be increased. These NK cells, and particularly CD56dim NK cells, with higher NKG2A expression showed features of functional exhaustion and were associated with a poor prognosis. The increase in NKG2A expression might be induced by IL-10, which was present at a high level in the plasma of HCC patients. Blocking IL-10 could specifically inhibit NKG2A expression in NK cells. Conclusions: These findings indicate that NKG2A expression is influenced by factors from cancer nests and contributes to NK cell exhaustion, suggesting that NKG2A blockade has the potential to restore immunity against liver tumors by reversing NK cell exhaustion.
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Affiliation(s)
- Cheng Sun
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jing Xu
- Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China , Guangzhou, China
| | - Qiang Huang
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China
| | - Mei Huang
- Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, Anhui Provincial Hospital Affiliated to Anhui Medical University , Hefei, China
| | - Hao Wen
- Xinjiang Key Laboratory of Echinococcosis, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University , Urumqi, China
| | - Chuanshan Zhang
- Xinjiang Key Laboratory of Echinococcosis, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University , Urumqi, China
| | - Jinyu Wang
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China , Hefei, Anhui, China
| | - Jiaxi Song
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China , Hefei, Anhui, China
| | - Meijuan Zheng
- Department of Clinical Laboratory, First Affiliated Hospital of Anhui Medical University , Hefei, China
| | - Haoyu Sun
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China , Hefei, Anhui, China
| | - Haiming Wei
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China , Hefei, Anhui, China
| | - Weihua Xiao
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China , Hefei, Anhui, China
| | - Rui Sun
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhigang Tian
- Institute of Immunology, The Key Laboratory of Innate Immunity and Chronic Disease (Chinese Academy of Medical Science), School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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Immunosuppression in liver tumors: opening the portal to effective immunotherapy. Cancer Gene Ther 2016; 24:114-120. [DOI: 10.1038/cgt.2016.54] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 09/01/2016] [Indexed: 12/11/2022]
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Asadi-Saghandi A, Shams A, Eslami G, Mirghanizadeh SA, Eskandari-Nasab E. Peginterferon Alfa-2a/Ribavirin treatment efficacy in chronic hepatitis C patients is related to natural killer group 2D gene rs1049174 GC polymorphism. Virusdisease 2016; 27:369-374. [PMID: 28004016 DOI: 10.1007/s13337-016-0349-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2016] [Accepted: 09/20/2016] [Indexed: 12/15/2022] Open
Abstract
Natural killer group 2D (NKG2D), as an activating receptor, plays pivotal role in viral infectious diseases. Several single nucleotide polymorphisms (SNPs) in the NKG2D gene have characterized that the rs1049174G/C SNP of NKG2D is in the spotlight of notice because of its role in activating of human T cells. This study aimed to investigate rs1049174G/C genetic polymorphism in Chronic Hepatitis C (CHC) patients. The study compromised 107 CHC patients with genotype 1a and 1b. All recruited patients were under treatment with Peginterferon Alfa-2a/Ribavirin according to standard protocol. After completing treatment, 67 patients showed sustained virologic response (SVR) and the rest of patients did not respond to the treatment and considered as non-responder (NR). Genotyping of NKG2D rs1049174G/C SNP was performed using PCR-RFLP method in SVR and NR patients. The NKG2D rs1049174 genotypes frequency for GG, GC and CC were 45, 41 and 14 % respectively. Genotypes distribution were significantly different between SVR and NR groups (p = 0.005). So that the patients with the homozygous GG genotype demonstrated a higher response to Peginterferon Alfa-2a/Ribavirin therapy against HCV infection (OR = 6.0, 95 %CI 1.71-21.08, p = 0.005). In conclusion, the rs1049174 GG genotype of NKG2D receptor is an effective factor in successfully treatment of CHC patients by Peginterferon Alfa-2a/Ribavirin.
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Affiliation(s)
- Abolghasem Asadi-Saghandi
- Department of Immunology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ali Shams
- Department of Immunology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Gilda Eslami
- Department of Parasitology and Mycology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyed Ali Mirghanizadeh
- Department of Immunology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Ebrahim Eskandari-Nasab
- Department of Clinical Biochemistry, Faculty of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran
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