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Fu H, Pickering H, Rubbi L, Ross TM, Zhou W, Reed EF, Pellegrini M. The response to influenza vaccination is associated with DNA methylation-driven regulation of T cell innate antiviral pathways. Clin Epigenetics 2024; 16:114. [PMID: 39169387 PMCID: PMC11340180 DOI: 10.1186/s13148-024-01730-x] [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: 04/25/2024] [Accepted: 08/12/2024] [Indexed: 08/23/2024] Open
Abstract
BACKGROUND The effect of vaccination on the epigenome remains poorly characterized. In previous research, we identified an association between seroprotection against influenza and DNA methylation at sites associated with the RIG-1 signaling pathway, which recognizes viral double-stranded RNA and leads to a type I interferon response. However, these studies did not fully account for confounding factors including age, gender, and BMI, along with changes in cell-type composition. RESULTS Here, we studied the influenza vaccine response in a longitudinal cohort vaccinated over two consecutive years (2019-2020 and 2020-2021), using peripheral blood mononuclear cells and a targeted DNA methylation approach. To address the effects of multiple factors on the epigenome, we designed a multivariate multiple regression model that included seroprotection levels as quantified by the hemagglutination-inhibition (HAI) assay test. CONCLUSIONS Our findings indicate that 179 methylation sites can be combined as potential signatures to predict seroprotection. These sites were not only enriched for genes involved in the regulation of the RIG-I signaling pathway, as found previously, but also enriched for other genes associated with innate immunity to viruses and the transcription factor binding sites of BRD4, which is known to impact T cell memory. We propose a model to suggest that the RIG-I pathway and BRD4 could potentially be modulated to improve immunization strategies.
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Affiliation(s)
- Hongxiang Fu
- Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
- Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Harry Pickering
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Liudmilla Rubbi
- Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
| | - Ted M Ross
- Department of Infectious Diseases, University of Georgia, Athens, GA, USA
- Center for Vaccines and Immunology, University of Georgia, Athens, GA, USA
| | - Wanding Zhou
- Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Elaine F Reed
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Matteo Pellegrini
- Department of Molecular Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.
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Symmonds J, Gaufin T, Xu C, Raehtz KD, Ribeiro RM, Pandrea I, Apetrei C. Making a Monkey out of Human Immunodeficiency Virus/Simian Immunodeficiency Virus Pathogenesis: Immune Cell Depletion Experiments as a Tool to Understand the Immune Correlates of Protection and Pathogenicity in HIV Infection. Viruses 2024; 16:972. [PMID: 38932264 PMCID: PMC11209256 DOI: 10.3390/v16060972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 05/31/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Understanding the underlying mechanisms of HIV pathogenesis is critical for designing successful HIV vaccines and cure strategies. However, achieving this goal is complicated by the virus's direct interactions with immune cells, the induction of persistent reservoirs in the immune system cells, and multiple strategies developed by the virus for immune evasion. Meanwhile, HIV and SIV infections induce a pandysfunction of the immune cell populations, making it difficult to untangle the various concurrent mechanisms of HIV pathogenesis. Over the years, one of the most successful approaches for dissecting the immune correlates of protection in HIV/SIV infection has been the in vivo depletion of various immune cell populations and assessment of the impact of these depletions on the outcome of infection in non-human primate models. Here, we present a detailed analysis of the strategies and results of manipulating SIV pathogenesis through in vivo depletions of key immune cells populations. Although each of these methods has its limitations, they have all contributed to our understanding of key pathogenic pathways in HIV/SIV infection.
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Affiliation(s)
- Jen Symmonds
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (J.S.); (C.X.); (K.D.R.); (I.P.)
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Thaidra Gaufin
- Tulane National Primate Research Center, Tulane University, Covington, LA 70433, USA;
| | - Cuiling Xu
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (J.S.); (C.X.); (K.D.R.); (I.P.)
- Division of Infectious Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Kevin D. Raehtz
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (J.S.); (C.X.); (K.D.R.); (I.P.)
- Division of Infectious Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Ruy M. Ribeiro
- Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545, USA
| | - Ivona Pandrea
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (J.S.); (C.X.); (K.D.R.); (I.P.)
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Cristian Apetrei
- Department of Infectious Diseases and Microbiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Division of Infectious Diseases, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
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3
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Zhang H, Yang Y, Cao Y, Guan J. Effects of chronic stress on cancer development and the therapeutic prospects of adrenergic signaling regulation. Biomed Pharmacother 2024; 175:116609. [PMID: 38678960 DOI: 10.1016/j.biopha.2024.116609] [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: 01/19/2024] [Revised: 04/14/2024] [Accepted: 04/17/2024] [Indexed: 05/01/2024] Open
Abstract
Long-term chronic stress is an important factor in the poor prognosis of cancer patients. Chronic stress reduces the tissue infiltration of immune cells in the tumor microenvironment (TME) by continuously activating the adrenergic signaling, inhibits antitumor immune response and tumor cell apoptosis while also inducing epithelial-mesenchymal transition (EMT) and tumor angiogenesis, promoting tumor invasion and metastasis. This review first summarizes how adrenergic signaling activates intracellular signaling by binding different adrenergic receptor (AR) heterodimers. Then, we focused on reviewing adrenergic signaling to regulate multiple functions of immune cells, including cell differentiation, migration, and cytokine secretion. In addition, the article discusses the mechanisms by which adrenergic signaling exerts pro-tumorigenic effects by acting directly on the tumor itself. It also highlights the use of adrenergic receptor modulators in cancer therapy, with particular emphasis on their potential role in immunotherapy. Finally, the article reviews the beneficial effects of stress intervention measures on cancer treatment. We think that enhancing the body's antitumor response by adjusting adrenergic signaling can enhance the efficacy of cancer treatment.
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Affiliation(s)
- Hao Zhang
- Department of Oncology, The Eighth Medical Center, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100091, China; Department of Oncology, The Fifth Medical Center, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100071, China.
| | - Yuwei Yang
- College of Pulmonary & Critical Care Medicine, Chinese PLA General Hospital, Beijing Key Laboratory of OTIR, Beijing, 100091, China.
| | - Yan Cao
- College of Pulmonary & Critical Care Medicine, Chinese PLA General Hospital, Beijing Key Laboratory of OTIR, Beijing, 100091, China.
| | - Jingzhi Guan
- Department of Oncology, The Fifth Medical Center, Chinese PLA (People's Liberation Army) General Hospital, Beijing 100071, China.
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Fu H, Pickering H, Rubbi L, Ross TM, Zhou W, Reed EF, Pellegrini M. The response to influenza vaccination is associated with DNA methylation-driven regulation of T cell innate antiviral pathways. RESEARCH SQUARE 2024:rs.3.rs-4324518. [PMID: 38826189 PMCID: PMC11142309 DOI: 10.21203/rs.3.rs-4324518/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Background The effect of vaccination on the epigenome remains poorly characterized. In previous research, we identified an association between seroprotection against influenza and DNA methylation at sites associated with the RIG-1 signaling pathway, which recognizes viral double-stranded RNA and leads to a type I interferon response. However, these studies did not fully account for confounding factors including age, gender, and BMI, along with changes in cell type composition. Results Here, we studied the influenza vaccine response in a longitudinal cohort vaccinated over two consecutive years (2019-2020 and 2020-2021), using peripheral blood mononuclear cells and a targeted DNA methylation approach. To address the effects of multiple factors on the epigenome, we designed a multivariate multiple regression model that included seroprotection levels as quantified by the hemagglutination-inhibition (HAI) assay test. Conclusions Our findings indicate that 179 methylation sites can be combined as potential signatures to predict seroprotection. These sites were not only enriched for genes involved in the regulation of the RIG-I signaling pathway, as found previously, but also enriched for other genes associated with innate immunity to viruses and the transcription factor binding sites of BRD4, which is known to impact T cell memory. We propose a model to suggest that the RIG-I pathway and BRD4 could potentially be modulated to improve immunization strategies.
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5
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Vivier E, Rebuffet L, Narni-Mancinelli E, Cornen S, Igarashi RY, Fantin VR. Natural killer cell therapies. Nature 2024; 626:727-736. [PMID: 38383621 DOI: 10.1038/s41586-023-06945-1] [Citation(s) in RCA: 92] [Impact Index Per Article: 92.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 12/06/2023] [Indexed: 02/23/2024]
Abstract
Natural killer (NK) cells are lymphocytes of the innate immune system. A key feature of NK cells is their ability to recognize a wide range of cells in distress, particularly tumour cells and cells infected with viruses. They combine both direct effector functions against their cellular targets and participate in the generation, shaping and maintenance of a multicellular immune response. As our understanding has deepened, several therapeutic strategies focused on NK cells have been conceived and are currently in various stages of development, from preclinical investigations to clinical trials. Here we explore in detail the complexity of NK cell biology in humans and highlight the role of these cells in cancer immunity. We also analyse the harnessing of NK cell immunity through immune checkpoint inhibitors, NK cell engagers, and infusions of preactivated or genetically modified, autologous or allogeneic NK cell products.
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Affiliation(s)
- Eric Vivier
- Innate Pharma Research Laboratories, Innate Pharma, Marseille, France.
- Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France.
- APHM, Hôpital de la Timone, Marseille-Immunopôle, Marseille, France.
- Paris-Saclay Cancer Cluster, Le Kremlin-Bicêtre, France.
| | - Lucas Rebuffet
- Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Emilie Narni-Mancinelli
- Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France
| | - Stéphanie Cornen
- Innate Pharma Research Laboratories, Innate Pharma, Marseille, France
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Siriratnam P, Huda S, Butzkueven H, van der Walt A, Jokubaitis V, Monif M. A comprehensive review of the advances in neuromyelitis optica spectrum disorder. Autoimmun Rev 2023; 22:103465. [PMID: 37852514 DOI: 10.1016/j.autrev.2023.103465] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 10/13/2023] [Indexed: 10/20/2023]
Abstract
Neuromyelitis optica spectrum disorder (NMOSD) is a rare relapsing neuroinflammatory autoimmune astrocytopathy, with a predilection for the optic nerves and spinal cord. Most cases are characterised by aquaporin-4-antibody positivity and have a relapsing disease course, which is associated with accrual of disability. Although the prognosis in NMOSD has improved markedly over the past few years owing to advances in diagnosis and therapeutics, it remains a severe disease. In this article, we review the evolution of our understanding of NMOSD, its pathogenesis, clinical features, disease course, treatment options and associated symptoms. We also address the gaps in knowledge and areas for future research focus.
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Affiliation(s)
- Pakeeran Siriratnam
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
| | - Saif Huda
- Department of Neurology, Walton Centre NHS Foundation Trust, Liverpool, UK
| | - Helmut Butzkueven
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
| | - Anneke van der Walt
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
| | - Vilija Jokubaitis
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, Victoria, Australia
| | - Mastura Monif
- Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; Department of Neurology, Alfred Health, Melbourne, Victoria, Australia; Department of Neurology, The Royal Melbourne Hospital, Parkville, VIC, Australia.
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Miliotou AN, Georgiou-Siafis SK, Ntenti C, Pappas IS, Papadopoulou LC. Recruiting In Vitro Transcribed mRNA against Cancer Immunotherapy: A Contemporary Appraisal of the Current Landscape. Curr Issues Mol Biol 2023; 45:9181-9214. [PMID: 37998753 PMCID: PMC10670245 DOI: 10.3390/cimb45110576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Revised: 11/05/2023] [Accepted: 11/14/2023] [Indexed: 11/25/2023] Open
Abstract
Over 100 innovative in vitro transcribed (IVT)-mRNAs are presently undergoing clinical trials, with a projected substantial impact on the pharmaceutical market in the near future. Τhe idea behind this is that after the successful cellular internalization of IVT-mRNAs, they are subsequently translated into proteins with therapeutic or prophylactic relevance. Simultaneously, cancer immunotherapy employs diverse strategies to mobilize the immune system in the battle against cancer. Therefore, in this review, the fundamental principles of IVT-mRNA to its recruitment in cancer immunotherapy, are discussed and analyzed. More specifically, this review paper focuses on the development of mRNA vaccines, the exploitation of neoantigens, as well as Chimeric Antigen Receptor (CAR) T-Cells, showcasing their clinical applications and the ongoing trials for the development of next-generation immunotherapeutics. Furthermore, this study investigates the synergistic potential of combining the CAR immunotherapy and the IVT-mRNAs by introducing our research group novel, patented delivery method that utilizes the Protein Transduction Domain (PTD) technology to transduce the IVT-mRNAs encoding the CAR of interest into the Natural Killer (NK)-92 cells, highlighting the potential for enhancing the CAR NK cell potency, efficiency, and bioenergetics. While IVT-mRNA technology brings exciting progress to cancer immunotherapy, several challenges and limitations must be acknowledged, such as safety, toxicity, and delivery issues. This comprehensive exploration of IVT-mRNA technology, in line with its applications in cancer therapeutics, offers valuable insights into the opportunities and challenges in the evolving landscape of cancer immunotherapy, setting the stage for future advancements in the field.
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Affiliation(s)
- Androulla N. Miliotou
- Laboratory of Pharmacology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece; (A.N.M.); (S.K.G.-S.); (C.N.)
- Department of Health Sciences, KES College, 1055 Nicosia, Cyprus
- Faculty of Pharmacy, Department of Health Sciences, University of Nicosia, 1700 Nicosia, Cyprus
| | - Sofia K. Georgiou-Siafis
- Laboratory of Pharmacology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece; (A.N.M.); (S.K.G.-S.); (C.N.)
- Laboratory of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Thessaly, 43100 Karditsa, Thessaly, Greece;
| | - Charikleia Ntenti
- Laboratory of Pharmacology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece; (A.N.M.); (S.K.G.-S.); (C.N.)
- 1st Laboratory of Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece
| | - Ioannis S. Pappas
- Laboratory of Pharmacology and Toxicology, Faculty of Veterinary Medicine, University of Thessaly, 43100 Karditsa, Thessaly, Greece;
| | - Lefkothea C. Papadopoulou
- Laboratory of Pharmacology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece; (A.N.M.); (S.K.G.-S.); (C.N.)
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8
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Yang Y, Lu Y, Jiang B. Population-weighted exposure to green spaces tied to lower COVID-19 mortality rates: A nationwide dose-response study in the USA. THE SCIENCE OF THE TOTAL ENVIRONMENT 2022; 851:158333. [PMID: 36041607 PMCID: PMC9420198 DOI: 10.1016/j.scitotenv.2022.158333] [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: 04/22/2022] [Revised: 08/23/2022] [Accepted: 08/23/2022] [Indexed: 05/29/2023]
Abstract
The COVID-19 pandemic has caused a huge loss of human life globally. However, few studies investigated the link between exposure to green space and risk of COVID-19 mortality rate, while also distinguishing the effects of various types of green space, considering the spatial distribution of human population and green space, and identifying the optimal buffer distances of nearby green space. It is critical and pressing to fill these significant knowledge gaps to protect and promote billions of people's health and life across the world. This study adopted a negative binomial generalized linear mixed-effects model to examine the association between the ratios of various types of green space, population-weighted exposure to those various types of green space, and COVID-19 mortality rates across 3025 counties in the USA, adjusted for sociodemographic, pre-existing chronic disease, policy and regulation, behavioral, and environmental factors. The findings show that greater exposure to forest was associated with lower COVID-19 mortality rates, while developed open space had mixed associations with COVID-19 mortality rates. Forest outside park had the largest effect size across all buffer distances, followed by forest inside park. The optimal exposure buffer distance was 1 km for forest outside park, with per one-unit of increase in exposure associated with a 9.9 % decrease in COVID-19 mortality rates (95 % confidence interval (CI): 6.9 %-12.8 %). The optimal exposure buffer distance of forest inside park was 400 m, with per one-unit of increase in exposure associated with a 4.7 % decrease in mortality rates (95 % CI: 2.4 %-6.9 %). The results suggest that greater exposure to green spaces, especially to nearby forests, may mitigate the risk of COVID-19 mortality. Although findings of an ecological study cannot be directly used to guide medical interventions, this study may pave a critical new way for future research and practice across multiple disciplines.
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Affiliation(s)
- Yuwen Yang
- Urban Environments and Human Health Lab, HKUrbanLabs, Faculty of Architecture, The University of Hong Kong, Hong Kong SAR; Division of Landscape Architecture, Department of Architecture, The University of Hong Kong, Hong Kong SAR
| | - Yi Lu
- Department of Architecture and Civil Engineering, College of Engineering, City University of Hong Kong, Hong Kong SAR
| | - Bin Jiang
- Urban Environments and Human Health Lab, HKUrbanLabs, Faculty of Architecture, The University of Hong Kong, Hong Kong SAR; Division of Landscape Architecture, Department of Architecture, The University of Hong Kong, Hong Kong SAR.
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Panaampon J, Kariya R, Okada S. Elotuzumab, a potential therapeutic humanized anti-SLAMF7 monoclonal antibody, enhances natural killer cell-mediated killing of primary effusion lymphoma cells. Cancer Immunol Immunother 2022; 71:2497-2509. [PMID: 35262781 PMCID: PMC10991573 DOI: 10.1007/s00262-022-03177-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/15/2022] [Indexed: 10/18/2022]
Abstract
Primary effusion lymphoma (PEL) is a rare aggressive B-cell non-Hodgkin's lymphoma with no optimal treatment. Signaling lymphocytic activation molecule-F7 (SLAMF7, CD319), a type I transmembrane glycoprotein highly expressed in multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. SLAMF7 also expresses on several hematopoietic lineages including NK cells. Elotuzumab (Elo), a humanized antibody targeting SLAMF7, is approved by FDA for MM treatment. In this study, we analyzed the expression of SLAMF7 on seven PEL cell lines. All PEL cells and NK cells showed high expression of SLAMF7. NK cells were enriched from PBMCs of healthy donors by MACS and expanded by co-culturing with MHC-class I negative K562 cells in the presence of IL-2 and IL-15. Expanded NK cells showed direct killing, and Elo demonstrated potent ADCC against PEL in an Effector:Target (E:T) dependent manner. Surface expression of CD107a on NK cells also increased in the process of ADCC. We also examined SLAMF7 expression of NK subpopulations and found that the CD56+CD16+ NK subpopulation demonstrated the highest SLAMF7 expression. Full-length-Elo but not F(ab')2-Elo exerts direct engagement to the expressing SLAMF7 on NK cells, promotes CD107a expression, and further augments NK cytotoxicity toward PEL. Elo enhanced survival of PEL-bearing immunodeficient mice with adoptive transfer of human NK cells. Taken together, our results show that NK cells play roles in PEL killing, and Elo causes ADCC/SLAMF7 ligation to boost NK cytotoxicity against PEL, offering promising preclinical evidence of Elo as a therapeutic monoclonal antibody treatment for PEL.
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Affiliation(s)
- Jutatip Panaampon
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan
| | - Ryusho Kariya
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan.
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Mossad O, Blank T. Getting on in Old Age: How the Gut Microbiota Interferes With Brain Innate Immunity. Front Cell Neurosci 2021; 15:698126. [PMID: 34295223 PMCID: PMC8290125 DOI: 10.3389/fncel.2021.698126] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/14/2021] [Indexed: 11/26/2022] Open
Abstract
The immune system is crucial for defending against various invaders, such as pathogens, cancer cells or misfolded proteins. With increasing age, the diminishing immune response, known as immunosenescence, becomes evident. Concomitantly, some diseases like infections, autoimmune diseases, chronic inflammatory diseases and cancer, accumulate with age. Different cell types are part of the innate immunity response and produce soluble factors, cytokines, chemokines, and type I interferons. Improper maturation of innate immune cells or their dysfunction have been linked to numerous age-related diseases. In parallel to the occurrence of the many functional facets of the immune response, a symbiotic microbiota had been acquired. For the relevant and situation-dependent function of the immune system the microbiome plays an essential role because it fine-tunes the immune system and its responses during life. Nevertheless, how the age-related alterations in the microbiota are reflected in the innate immune system, is still poorly understood. With this review, we provide an up-to-date overview on our present understanding of the gut microbiota effects on innate immunity, with a particular emphasis on aging-associated changes in the gut microbiota and the implications for the brain innate immune response.
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Affiliation(s)
- Omar Mossad
- Faculty of Medicine, Institute of Neuropathology, University of Freiburg, Freiburg, Germany
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Thomas Blank
- Faculty of Medicine, Institute of Neuropathology, University of Freiburg, Freiburg, Germany
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11
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Nakano-Narusawa Y, Yokohira M, Yamakawa K, Ye J, Tanimoto M, Wu L, Mukai Y, Imaida K, Matsuda Y. Relationship between Lung Carcinogenesis and Chronic Inflammation in Rodents. Cancers (Basel) 2021; 13:cancers13122910. [PMID: 34200786 PMCID: PMC8230400 DOI: 10.3390/cancers13122910] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 06/01/2021] [Accepted: 06/08/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Lung cancer is the most common cause of cancer-related deaths worldwide. There are various risk factors for lung cancer, including tobacco smoking, inhalation of dust particles, chronic inflammation, and genetic factors. Chronic inflammation has been considered a key factor that promotes tumor progression via production of cytokines, chemokines, cytotoxic mediators, and reactive oxygen species by inflammatory cells. Here, we review rodent models of lung tumor induced by tobacco, tobacco-related products, and pro-inflammatory materials as well as genetic modifications, and discuss the relationship between chronic inflammation and lung tumor. Through this review, we hope to clarify the effects of chronic inflammation on lung carcinogenesis and help develop new treatments for lung cancer. Abstract Lung cancer remains the leading cause of cancer-related deaths, with an estimated 1.76 million deaths reported in 2018. Numerous studies have focused on the prevention and treatment of lung cancer using rodent models. Various chemicals, including tobacco-derived agents induce lung cancer and pre-cancerous lesions in rodents. In recent years, transgenic engineered rodents, in particular, those generated with a focus on the well-known gene mutations in human lung cancer (KRAS, EGFR, and p53 mutations) have been widely studied. Animal studies have revealed that chronic inflammation significantly enhances lung carcinogenesis, and inhibition of inflammation suppresses cancer progression. Moreover, the reduction in tumor size by suppression of inflammation in animal experiments suggests that chronic inflammation influences the promotion of tumorigenesis. Here, we review rodent lung tumor models induced by various chemical carcinogens, including tobacco-related carcinogens, and transgenics, and discuss the roles of chronic inflammation in lung carcinogenesis.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yoko Matsuda
- Correspondence: ; Tel.: +81-87-891-2109; Fax: +81-87-891-2112
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12
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Han Y, Gao H, Xu J, Luo J, Han B, Bao J, Pan G, Li T, Zhou Z. Innate and Adaptive Immune Responses Against Microsporidia Infection in Mammals. Front Microbiol 2020; 11:1468. [PMID: 32670257 PMCID: PMC7332555 DOI: 10.3389/fmicb.2020.01468] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 06/04/2020] [Indexed: 12/22/2022] Open
Abstract
Microsporidia are obligate intracellular and eukaryotic pathogens that can infect immunocompromised and immunocompetent mammals, including humans. Both innate and adaptive immune systems play important roles against microsporidian infection. The innate immune system can partially eliminate the infection by immune cells, such as gamma delta T cell, natural killer cells (NKs), macrophages and dendritic cells (DCs), and present the pathogens to lymphocytes. The innate immune cells can also prime and enhance the adaptive immune response via surface molecules and secreted cytokines. The adaptive immune system is critical to eliminate microsporidian infection by activating cytotoxic T lymphocyte (CTL) and humoral immune responses, and feedback regulation of the innate immune mechanism. In this review, we will discuss the cellular and molecular responses and functions of innate and adaptive immune systems against microsporidian infection.
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Affiliation(s)
- Yinze Han
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Hailong Gao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Jinzhi Xu
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Jian Luo
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Bing Han
- Department of Pathology, Albert Einstein College of Medicine, The Bronx, NY, United States
| | - Jialing Bao
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Guoqing Pan
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Tian Li
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China
| | - Zeyang Zhou
- State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China.,Chongqing Key Laboratory of Microsporidia Infection and Control, Southwest University, Chongqing, China.,College of Life Sciences, Chongqing Normal University, Chongqing, China
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13
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Ortega-Rodríguez AC, Marín-Jáuregui LS, Martínez-Shio E, Hernández Castro B, González-Amaro R, Escobedo-Uribe CD, Monsiváis-Urenda AE. Altered NK cell receptor repertoire and function of natural killer cells in patients with acute myocardial infarction: A three-month follow-up study. Immunobiology 2020; 225:151909. [PMID: 32051096 DOI: 10.1016/j.imbio.2020.151909] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 01/29/2020] [Indexed: 01/09/2023]
Abstract
NK cells are important in the onset of acute myocardial infarction (AMI) by their ability to secrete IFN-γ and other inflammatory cytokines. They also participate in regulating pathological cardiac remodeling after myocardial infarction. Mechanisms of regulation, however, are incompletely understood. Herein, the aim of this study is to explore the possible association between the expression pattern of different NK cell receptors (phenotype), as well as the cytotoxic function of NK cells from AMI patients with their myocardial function after three months follow-up. We analyzed the phenotype and function of both CD56dimCD16+ and CD56brightCD16- NK cells from twenty-one patients within the first 72 h after ST-elevation AMI and three-month follow-up, as well as fifteen healthy controls. Clinical characteristics and ventricular function determined by echocardiography were also evaluated. NK cells from AMI patients showed an activated phenotype, characterized by high TNF-α production and low percentages of the activating receptor NKG2D. Interestingly, AMI patients display higher levels of circulating IL-10+ NK cells. Three-month follow-up showed that NK cells exhibit a diminished cytotoxic function. These data show that NK cells may have a role mediating myocardial remodeling by regulating the inflammatory response, mainly by the production of IL-10. We also propose that NKG2D may have a role in the onset of the inflammatory response immediately after AMI. The precise regulation of NK cells function may represent an important step in recovery of myocardial function.
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Affiliation(s)
- Alma Celeste Ortega-Rodríguez
- Medicina Molecular y Traslacional, Centro de Investigación en Ciencias de la Salud y Biomedicina, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Mexico
| | - Laura Sherell Marín-Jáuregui
- Medicina Molecular y Traslacional, Centro de Investigación en Ciencias de la Salud y Biomedicina, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Mexico
| | - Elena Martínez-Shio
- Medicina Molecular y Traslacional, Centro de Investigación en Ciencias de la Salud y Biomedicina, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Mexico
| | - Berenice Hernández Castro
- Medicina Molecular y Traslacional, Centro de Investigación en Ciencias de la Salud y Biomedicina, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Mexico
| | - Roberto González-Amaro
- Medicina Molecular y Traslacional, Centro de Investigación en Ciencias de la Salud y Biomedicina, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Mexico
| | | | - Adriana E Monsiváis-Urenda
- Medicina Molecular y Traslacional, Centro de Investigación en Ciencias de la Salud y Biomedicina, Facultad de Medicina, Universidad Autónoma de San Luis Potosí, Mexico.
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14
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Saparbay J, Tanaka Y, Tanimine N, Ohira M, Ohdan H. Everolimus enhances TRAIL‐mediated anti‐tumor activity of liver resident natural killer cells in mice. Transpl Int 2019; 33:229-243. [DOI: 10.1111/tri.13536] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 06/04/2019] [Accepted: 09/21/2019] [Indexed: 11/29/2022]
Affiliation(s)
- Jamilya Saparbay
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
| | - Yuka Tanaka
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
| | - Naoki Tanimine
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
- Department of Surgery Center for Transplantation Sciences Massachusetts General Hospital Boston MA USA
| | - Masahiro Ohira
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
- Division of Regeneration and Medicine Medical Center for Translational and Clinical Research Hiroshima University Hospital Hiroshima Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery Applied Life Sciences Institute of Biomedical & Health Sciences Hiroshima University Hiroshima Japan
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15
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Hassan MIA, Voigt K. Pathogenicity patterns of mucormycosis: epidemiology, interaction with immune cells and virulence factors. Med Mycol 2019; 57:S245-S256. [PMID: 30816980 PMCID: PMC6394756 DOI: 10.1093/mmy/myz011] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 12/20/2018] [Accepted: 02/13/2019] [Indexed: 12/14/2022] Open
Abstract
Fungi of the basal lineage order Mucorales are able to cause infections in animals and humans. Mucormycosis is a well-known, life-threatening disease especially in patients with a compromised immune system. The rate of mortality and morbidity caused by mucormycosis has increased rapidly during the last decades, especially in developing countries. The systematic, phylogenetic, and epidemiological distributions of mucoralean fungi are addressed in relation to infection in immunocompromised patients. The review highlights the current achievements in (i) diagnostics and management of mucormycosis, (ii) the study of the interaction of Mucorales with cells of the innate immune system, (iii) the assessment of the virulence of Mucorales in vertebrate and invertebrate infection models, and (iv) the determination of virulence factors that are key players in the infection process, for example, high-affinity iron permease (FTR1), spore coat protein (CotH), alkaline Rhizopus protease enzyme (ARP), ADP-ribosylation factor (ARF), dihydrolipoyl dehydrogenase, calcineurin (CaN), serine and aspartate proteases (SAPs). The present mini-review attempts to increase the awareness of these difficult-to-manage fungal infections and to encourage research in the detection of ligands and receptors as potential diagnostic parameters and drug targets.
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Affiliation(s)
- Mohamed I Abdelwahab Hassan
- Jena Microbial Resource Collection, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Adolf-Reichwein-Strasse 23, 07745 Jena, Germany
- Department of Microbiology and Molecular Biology, Institute of Microbiology, Faculty of Biological Sciences, University of Jena, Neugasse 25, 07743 Jena, Germany
- Pests and Plant Protection Department, National Research Centre, 33rd El Buhouth Street (Postal code: 12622) Dokki, Giza, Egypt
| | - Kerstin Voigt
- Jena Microbial Resource Collection, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knoell Institute, Adolf-Reichwein-Strasse 23, 07745 Jena, Germany
- Department of Microbiology and Molecular Biology, Institute of Microbiology, Faculty of Biological Sciences, University of Jena, Neugasse 25, 07743 Jena, Germany
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16
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Ignacio A, Breda CNS, Camara NOS. Innate lymphoid cells in tissue homeostasis and diseases. World J Hepatol 2017; 9:979-989. [PMID: 28878863 PMCID: PMC5569277 DOI: 10.4254/wjh.v9.i23.979] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 05/22/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023] Open
Abstract
Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells. They are a part of the innate immune system, but develop from the lymphoid lineage. They lack pattern-recognition receptors and rearranged receptors, and therefore cannot directly mediate antigen specific responses. The progenitors specifically associated with the ILCs lineage have been uncovered, enabling the distinction between ILCs and natural killer cells. Based on the requirement of specific transcription factors and their patterns of cytokine production, ILCs are categorized into three subsets (ILC1, ILC2 and ILC3). First observed in mucosal surfaces, these cell populations interact with hematopoietic and non-hematopoietic cells throughout the body during homeostasis and diseases, promoting immunity, commensal microbiota tolerance, tissue repair and inflammation. Over the last 8 years, ILCs came into the spotlight as an essential cell type able to integrate diverse host immune responses. Recently, it became known that ILC subsets play a key role in immune responses at barrier surfaces, interacting with the microbiota, nutrients and metabolites. Since the liver receives the venous blood directly from the intestinal vein, the intestine and liver are essential to maintain tolerance and can rapidly respond to infections or tissue damage. Therefore, in this review, we discuss recent findings regarding ILC functions in homeostasis and disease, with a focus on the intestine and liver.
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Affiliation(s)
- Aline Ignacio
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Cristiane Naffah Souza Breda
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, SP 05508-900, Brazil
| | - Niels Olsen Saraiva Camara
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, SP 05508-900, Brazil.
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17
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Robinette ML, Colonna M. Innate lymphoid cells and the MHC. HLA 2016; 87:5-11. [PMID: 26812060 DOI: 10.1111/tan.12723] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Accepted: 11/24/2015] [Indexed: 12/29/2022]
Abstract
Innate lymphoid cells (ILCs) are a new class of immune cells that include natural killer (NK) cells and appear to be the innate counterparts to CD4(+) helper T cells and CD8(+) cytotoxic T cells based on developmental and functional similarities. Like T cells, both NK cells and other ILCs also show connections to the major histocompatibility complex (MHC). In human and mouse, NK cells recognize and respond to classical and nonclassical MHC I molecules as well as structural homologues, whereas mouse ILCs have recently been shown to express MHC II. We describe the history of MHC I recognition by NK cells and discuss emerging roles for MHC II expression by ILC subsets, making comparisons between both mouse and human when possible.
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Affiliation(s)
- M L Robinette
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
| | - M Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, USA
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18
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Dunn GP, Okada H. Principles of immunology and its nuances in the central nervous system. Neuro Oncol 2016; 17 Suppl 7:vii3-vii8. [PMID: 26516224 DOI: 10.1093/neuonc/nov175] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Cancer immunotherapy represents the biggest change in the cancer treatment landscape in the last several years. Indeed, the clinical successes in several cancer types have generated widespread enthusiasm that immune-based treatments may influence the management of patients with malignant brain tumors as well. A number of promising clinical trials in this area are currently ongoing in neuro-oncology, and a wave of additional efforts are sure to follow. However, the basic immunology underlying immunotherapy-and the nuances unique to the immunobiology in the central nervous system-is often not in the daily lexicon of the practicing neuro-oncologist and neurosurgeon. To this end, here we provide a timely and working overview of key principles of fundamental immunology as a pragmatic context for understanding where therapeutic efforts may act in the cellular dynamics of the immune response. Moreover, we review the issues of lymphatic drainage, antigen presentation, and the blood-brain barrier as considerations that are germane to thinking about immunity to tumors arising in the brain. Together, these topics will provide a foundation for the exciting efforts in immune-based treatments that will hopefully provide real benefit to brain tumor patients.
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Affiliation(s)
- Gavin P Dunn
- Department of Neurological Surgery, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri (G.P.D.); Department of Neurological Surgery, Brain Tumor Immunotherapy Center, University of California, San Francisco, Helen Diller Family Cancer Research Building HD 472, San Francisco, California (H.O.)
| | - Hideho Okada
- Department of Neurological Surgery, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri (G.P.D.); Department of Neurological Surgery, Brain Tumor Immunotherapy Center, University of California, San Francisco, Helen Diller Family Cancer Research Building HD 472, San Francisco, California (H.O.)
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19
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Pugh JL, Foster SA, Sukhina AS, Petravic J, Uhrlaub JL, Padilla‐Torres J, Hayashi T, Nakachi K, Smithey MJ, Nikolich‐Žugich J. Acute systemic DNA damage in youth does not impair immune defense with aging. Aging Cell 2016; 15:686-93. [PMID: 27072188 PMCID: PMC4933672 DOI: 10.1111/acel.12478] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/06/2016] [Indexed: 02/06/2023] Open
Abstract
Aging‐related decline in immunity is believed to be the main driver behind decreased vaccine efficacy and reduced resistance to infections in older adults. Unrepaired DNA damage is known to precipitate cellular senescence, which was hypothesized to be the underlying cause of certain age‐related phenotypes. Consistent with this, some hallmarks of immune aging were more prevalent in individuals exposed to whole‐body irradiation (WBI), which leaves no anatomical repository of undamaged hematopoietic cells. To decisively test whether and to what extent WBI in youth will leave a mark on the immune system as it ages, we exposed young male C57BL/6 mice to sublethal WBI (0.5–4 Gy), mimicking human survivor exposure during nuclear catastrophe. We followed lymphocyte homeostasis thorough the lifespan, response to vaccination, and ability to resist lethal viral challenge in the old age. None of the irradiated groups showed significant differences compared with mock‐irradiated (0 Gy) animals for the parameters measured. Even the mice that received the highest dose of sublethal WBI in youth (4 Gy) exhibited equilibrated lymphocyte homeostasis, robust T‐ and B‐cell responses to live attenuated West Nile virus (WNV) vaccine and full survival following vaccination upon lethal WNV challenge. Therefore, a single dose of nonlethal WBI in youth, resulting in widespread DNA damage and repopulation stress in hematopoietic cells, leaves no significant trace of increased immune aging in a lethal vaccine challenge model.
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Affiliation(s)
- Jason L. Pugh
- Department of Immunobiology University of Arizona College of Medicine Tucson AZ USA
- Arizona Center on Aging University of Arizona College of Medicine Tucson AZ USA
- Graduate Interdisciplinary Program in Genetics University of Arizona Tucson AZ USA
| | - Sarah A. Foster
- Department of Immunobiology University of Arizona College of Medicine Tucson AZ USA
| | - Alona S. Sukhina
- Department of Immunobiology University of Arizona College of Medicine Tucson AZ USA
| | - Janka Petravic
- Centre for Vascular Research University of New South Wales Sydney NSW 2052 Australia
| | - Jennifer L. Uhrlaub
- Department of Immunobiology University of Arizona College of Medicine Tucson AZ USA
- Arizona Center on Aging University of Arizona College of Medicine Tucson AZ USA
| | - Jose Padilla‐Torres
- Department of Immunobiology University of Arizona College of Medicine Tucson AZ USA
| | | | - Kei Nakachi
- Radiation Effects Research Foundation Minato‐Ku Hiroshima Japan
| | - Megan J. Smithey
- Department of Immunobiology University of Arizona College of Medicine Tucson AZ USA
- Arizona Center on Aging University of Arizona College of Medicine Tucson AZ USA
| | - Janko Nikolich‐Žugich
- Department of Immunobiology University of Arizona College of Medicine Tucson AZ USA
- Arizona Center on Aging University of Arizona College of Medicine Tucson AZ USA
- Graduate Interdisciplinary Program in Genetics University of Arizona Tucson AZ USA
- The BIO5 Institute University of Arizona Tucson AZ USA
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20
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Li K, Gordon AC, Zheng L, Li W, Guo Y, Sun J, Zhang G, Han G, Larson AC, Zhang Z. Clinically applicable magnetic-labeling of natural killer cells for MRI of transcatheter delivery to liver tumors: preclinical validation for clinical translation. Nanomedicine (Lond) 2016; 10:1761-74. [PMID: 26080698 DOI: 10.2217/nnm.15.24] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
AIM To test the hypothesis that MRI can monitor intraportal vein (IPV) transcatheter delivery of clinically applicable heparin-protamine-ferumoxytol (HPF) nanocomplex-labeled natural killer (NK) cells to liver tumor. MATERIALS & METHODS Liver tumor rat models underwent catheterization for IPV infusion of HPF-labeled NK cells (NK-92MI cell line). MRI measurements within tumor and adjacent liver tissues were compared pre- and post-NK cell infusion. Histology studies were used to identify NK cells in the target tumors. RESULTS For first time, we demonstrated that MRI tracks HPF-labeled NK cells migration within liver following IPV delivery. CONCLUSION IPV transcatheter infusion permitted selective delivery of NK cells to liver tissues and MRI allowed tracking NK cell biodistributions within the tumors.
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Affiliation(s)
- Kangan Li
- Department of Radiology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, P. R. China.,Departments of Radiology, Northwestern University, 737 N Michigan Ave, Suite 1600, Chicago, IL 60611, USA.,Robert H. Lurie Comprehensive Cancer Center, 675 N St Clair, 21st Floor, Suite 100, Chicago, IL 60611, USA
| | - Andrew C Gordon
- Departments of Radiology, Northwestern University, 737 N Michigan Ave, Suite 1600, Chicago, IL 60611, USA
| | - Linfeng Zheng
- Department of Radiology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, P. R. China.,Departments of Radiology, Northwestern University, 737 N Michigan Ave, Suite 1600, Chicago, IL 60611, USA.,Robert H. Lurie Comprehensive Cancer Center, 675 N St Clair, 21st Floor, Suite 100, Chicago, IL 60611, USA
| | - Weiguo Li
- Departments of Radiology, Northwestern University, 737 N Michigan Ave, Suite 1600, Chicago, IL 60611, USA
| | - Yang Guo
- Departments of Radiology, Northwestern University, 737 N Michigan Ave, Suite 1600, Chicago, IL 60611, USA
| | - Jing Sun
- Departments of Radiology, Northwestern University, 737 N Michigan Ave, Suite 1600, Chicago, IL 60611, USA
| | - Guixiang Zhang
- Department of Radiology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai 200080, P. R. China
| | - Guohong Han
- Department of Liver Disease & Digestive Interventional Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Andrew C Larson
- Departments of Radiology, Northwestern University, 737 N Michigan Ave, Suite 1600, Chicago, IL 60611, USA.,Robert H. Lurie Comprehensive Cancer Center, 675 N St Clair, 21st Floor, Suite 100, Chicago, IL 60611, USA
| | - Zhuoli Zhang
- Departments of Radiology, Northwestern University, 737 N Michigan Ave, Suite 1600, Chicago, IL 60611, USA.,Robert H. Lurie Comprehensive Cancer Center, 675 N St Clair, 21st Floor, Suite 100, Chicago, IL 60611, USA
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21
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Zhao D, Zhang Q, Liu Y, Li X, Zhao K, Ding Y, Li Z, Shen Q, Wang C, Li N, Cao X. H3K4me3 Demethylase Kdm5a Is Required for NK Cell Activation by Associating with p50 to Suppress SOCS1. Cell Rep 2016; 15:288-99. [PMID: 27050510 DOI: 10.1016/j.celrep.2016.03.035] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2015] [Revised: 01/21/2016] [Accepted: 03/09/2016] [Indexed: 01/25/2023] Open
Abstract
The H3K4me3 demethylase Kdm5a regulates gene transcription and is implicated in carcinogenesis. However, the role of Kdm5a in innate immune response remains poorly understood. Here, we demonstrate that Kdm5a deficiency impairs activation of natural killer (NK) cells, with decreased IFN-γ production. Accordingly, Kdm5a(-/-) mice are highly susceptible to Listeria monocytogenes (Lm) infection. During NK cell activation, loss of Kdm5a profoundly impairs phosphorylation and nuclear localization of STAT4, along with increased expression of suppressor of cytokine signaling 1 (SOCS1). Mechanistic studies reveal that Kdm5a associates with p50 and binds to the Socs1 promoter region in resting NK cells, leading to a substantial decrease in H3K4me3 modification and repressive chromatin configuration at the Socs1 promoter. Thus, Kdm5a is required for priming activation of NK cells by suppressing the suppressor, SOCS1. Our study provides insights into the epigenetic regulation of innate immune response of NK cells.
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Affiliation(s)
- Dezhi Zhao
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Qian Zhang
- National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China
| | - Yiqi Liu
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xia Li
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Kai Zhao
- National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yuanyuan Ding
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Zhiqing Li
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Qicong Shen
- National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China
| | - Chunmei Wang
- National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Nan Li
- National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China
| | - Xuetao Cao
- Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China; National Key Laboratory of Medical Molecular Biology and Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100730, China.
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22
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Scanzano A, Cosentino M. Adrenergic regulation of innate immunity: a review. Front Pharmacol 2015; 6:171. [PMID: 26321956 PMCID: PMC4534859 DOI: 10.3389/fphar.2015.00171] [Citation(s) in RCA: 248] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 07/31/2015] [Indexed: 12/24/2022] Open
Abstract
The sympathetic nervous system has a major role in the brain-immune cross-talk, but few information exist on the sympathoadrenergic regulation of innate immune system. The aim of this review is to summarize available knowledge regarding the sympathetic modulation of the innate immune response, providing a rational background for the possible repurposing of adrenergic drugs as immunomodulating agents. The cells of immune system express adrenoceptors (AR), which represent the target for noradrenaline and adrenaline. In human neutrophils, adrenaline and noradrenaline inhibit migration, CD11b/CD18 expression, and oxidative metabolism, possibly through β-AR, although the role of α1- and α2-AR requires further investigation. Natural Killer express β-AR, which are usually inhibitory. Monocytes express β-AR and their activation is usually antiinflammatory. On murine Dentritic cells (DC), β-AR mediate sympathetic influence on DC-T cells interactions. In human DC β2-AR may affect Th1/2 differentiation of CD4+ T cells. In microglia and in astrocytes, β2-AR dysregulation may contribute to neuroinflammation in autoimmune and neurodegenerative disease. In conclusion, extensive evidence supports a critical role for adrenergic mechanisms in the regulation of innate immunity, in peripheral tissues as well as in the CNS. Sympathoadrenergic pathways in the innate immune system may represent novel antiinflammatory and immunomodulating targets with significant therapeutic potential.
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Affiliation(s)
- Angela Scanzano
- Center for Research in Medical Pharmacology, University of Insubria Varese, Italy
| | - Marco Cosentino
- Center for Research in Medical Pharmacology, University of Insubria Varese, Italy
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23
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Abstract
Tumors cells can release natural killer (NK) cell ligands for activating receptor NKG2D that are thought to inhibit NK cell function. In a recent issue of Science, Deng et al. (2015) show that, unexpectedly, a soluble NKG2D ligand can enhance anti-tumor NK cell activity.
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Affiliation(s)
- Drew M Pardoll
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
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24
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Tu TC, Brown NK, Kim TJ, Wroblewska J, Yang X, Guo X, Lee SH, Kumar V, Lee KM, Fu YX. CD160 is essential for NK-mediated IFN-γ production. ACTA ACUST UNITED AC 2015; 212:415-29. [PMID: 25711213 PMCID: PMC4354368 DOI: 10.1084/jem.20131601] [Citation(s) in RCA: 87] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Tu et al. generated a novel CD160-deficient mouse and showed impaired NK cell–mediated tumor elimination and IFN-γ production. CD160+ NK cells are functionally distinct in secretion of IFN-γ from their CD160− NK cell counterparts. NK-derived cytokines play important roles for natural killer (NK) function, but how the cytokines are regulated is poorly understood. CD160 is expressed on activated NK or T cells in humans but its function is unknown. We generated CD160-deficient mice to probe its function. Although CD160−/− mice showed no abnormalities in lymphocyte development, the control of NK-sensitive tumors was severely compromised in CD160−/− mice. Surprisingly, the cytotoxicity of NK cells was not impaired, but interferon-γ (IFN-γ) secretion by NK cells was markedly reduced in CD160−/− mice. Functionally targeting CD160 signaling with a soluble CD160-Ig also impaired tumor control and IFN-γ production, suggesting an active role of CD160 signaling. Using reciprocal bone marrow transfer and cell culture, we have identified the intrinsic role of CD160 on NK cells, as well as its receptor on non-NK cells, for regulating cytokine production. To demonstrate sufficiency of the CD160+ NK cell subset in controlling NK-dependent tumor growth, intratumoral transfer of the CD160+ NK fraction led to tumor regression in CD160−/− tumor-bearing mice, indicating demonstrable therapeutic potential for controlling early tumors. Therefore, CD160 is not only an important biomarker but also functionally controls cytokine production by NK cells.
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Affiliation(s)
- Tony C Tu
- Department of Pathology, The University of Chicago, Chicago, IL 60637
| | - Nicholas K Brown
- Department of Pathology, The University of Chicago, Chicago, IL 60637
| | - Tae-Jin Kim
- Department of Pathology, The University of Chicago, Chicago, IL 60637 Global Research Lab, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-705, South Korea
| | - Joanna Wroblewska
- Department of Pathology, The University of Chicago, Chicago, IL 60637
| | - Xuanming Yang
- Department of Pathology, The University of Chicago, Chicago, IL 60637
| | - Xiaohuan Guo
- Department of Pathology, The University of Chicago, Chicago, IL 60637
| | - Seoyun Hyunji Lee
- Department of Pathology, The University of Chicago, Chicago, IL 60637 Global Research Lab, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-705, South Korea
| | - Vinay Kumar
- Department of Pathology, The University of Chicago, Chicago, IL 60637
| | - Kyung-Mi Lee
- Department of Pathology, The University of Chicago, Chicago, IL 60637 Global Research Lab, Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 136-705, South Korea Department of Melanoma Medical Oncology and Immunology, MD Anderson Cancer Center, Houston, TX 77054
| | - Yang-Xin Fu
- Department of Pathology, The University of Chicago, Chicago, IL 60637
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25
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Cella M, Miller H, Song C. Beyond NK cells: the expanding universe of innate lymphoid cells. Front Immunol 2014; 5:282. [PMID: 24982658 PMCID: PMC4058828 DOI: 10.3389/fimmu.2014.00282] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Accepted: 05/30/2014] [Indexed: 12/20/2022] Open
Abstract
For a long time, natural killer (NK) cells were thought to be the only innate immune lymphoid population capable of responding to invading pathogens under the influence of changing environmental cues. In the last few years, an increasing amount of evidence has shown that a number of different innate lymphoid cell (ILC) populations found at mucosal sites rapidly respond to locally produced cytokines in order to establish or maintain homeostasis. These ILC populations closely mirror the phenotype of adaptive T helper subsets in their repertoire of secreted soluble factors. Early in the immune response, ILCs are responsible for setting the stage to mount an adaptive T cell response that is appropriate for the incoming insult. Here, we review the diversity of ILC subsets and discuss similarities and differences between ILCs and NK cells in function and key transcriptional factors required for their development.
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Affiliation(s)
- Marina Cella
- Department of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO , USA
| | - Hannah Miller
- Department of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO , USA
| | - Christina Song
- Department of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO , USA
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Abstract
With an array of activating and inhibitory receptors, natural killer (NK) cells are involved in the eradication of infected, transformed, and tumor cells. NKp44 is a member of the natural cytotoxicity receptor family, which is exclusively expressed on activated NK cells. Here, we identify natural cytotoxicity receptor NKp44 (NKp44L), a novel isoform of the mixed-lineage leukemia-5 protein, as a cellular ligand for NKp44. Unlike the other MLL family members, NKp44L is excluded from the nucleus, but expressed at the cell-surface level; its subcellular localization is being associated with the presence of a specific C-terminal motif. Strikingly, NKp44L has not been detected on circulating cells isolated from healthy individuals, but it is expressed on a large panel of the tumor and transformed cells. The sharply decreased NK lysis activity induced by anti-NKp44L antibodies directly demonstrates the role of NKp44L in cytotoxicity. Taken together, these results show that NKp44L could be critical for NK cell-mediated innate immunity. The identification and cellular distribution of NKp44L highlight the role of this self-molecule as a danger signal to alert the NK cell network.
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27
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May RM, Okumura M, Hsu CJ, Bassiri H, Yang E, Rak G, Mace EM, Philip NH, Zhang W, Baumgart T, Orange JS, Nichols KE, Kambayashi T. Murine natural killer immunoreceptors use distinct proximal signaling complexes to direct cell function. Blood 2013; 121:3135-46. [PMID: 23407547 PMCID: PMC3630829 DOI: 10.1182/blood-2012-12-474361] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Accepted: 02/03/2013] [Indexed: 11/20/2022] Open
Abstract
Signaling pathways leading to natural killer (NK)-cell effector function are complex and incompletely understood. Here, we investigated the proximal signaling pathways downstream of the immunotyrosine-based activation motif (ITAM) bearing activating receptors. We found that the adaptor molecule SH2 domain-containing leukocyte protein of 76 kD (SLP-76) is recruited to microclusters at the plasma membrane in activated NK cells and that this is required for initiation of downstream signaling and multiple NK-cell effector functions in vitro and in vivo. Surprisingly, we found that 2 types of proximal signaling complexes involving SLP-76 were formed. In addition to the canonical membrane complex formed between SLP-76 and linker for activation of T cells (LAT) family members, a novel LAT family-independent SLP-76-dependent signaling pathway was identified. The LAT family-independent pathway involved the SH2 domain of SLP-76 and adhesion and degranulation-promoting adaptor protein (ADAP). Both the LAT family-dependent and ADAP-dependent pathway contributed to interferon-gamma production and cytotoxicity; however, they were not essential for other SLP-76-dependent events, including phosphorylation of AKT and extracellular signal-related kinase and cellular proliferation. These results demonstrate that NK cells possess an unexpected bifurcation of proximal ITAM-mediated signaling, each involving SLP-76 and contributing to optimal NK-cell function.
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MESH Headings
- Adaptor Proteins, Signal Transducing/analysis
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/immunology
- Adaptor Proteins, Signal Transducing/metabolism
- Amino Acid Transport System y+/immunology
- Amino Acid Transport System y+L
- Animals
- Cell Line, Tumor
- Cell Proliferation
- Cells, Cultured
- Fusion Regulatory Protein 1, Light Chains/immunology
- Interferon-gamma/immunology
- Killer Cells, Natural/cytology
- Killer Cells, Natural/immunology
- Killer Cells, Natural/metabolism
- MAP Kinase Signaling System
- Mice
- Mice, Inbred C57BL
- Mice, Inbred NOD
- Mice, Knockout
- NK Cell Lectin-Like Receptor Subfamily A/immunology
- Neoplasms/genetics
- Neoplasms/immunology
- Neoplasms/pathology
- Phosphoproteins/analysis
- Phosphoproteins/genetics
- Phosphoproteins/immunology
- Phosphoproteins/metabolism
- Phosphorylation
- Proto-Oncogene Proteins c-akt/immunology
- Signal Transduction
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Affiliation(s)
- Rebecca M May
- Division of Transfusion Medicine and Therapeutic Pathology, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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28
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Senba M, Mori N. Mechanisms of virus immune evasion lead to development from chronic inflammation to cancer formation associated with human papillomavirus infection. Oncol Rev 2012; 6:e17. [PMID: 25992215 PMCID: PMC4419623 DOI: 10.4081/oncol.2012.e17] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2012] [Revised: 08/02/2012] [Accepted: 08/03/2012] [Indexed: 12/11/2022] Open
Abstract
Human papillomavirus (HPV) has developed strategies to escape eradication by innate and adaptive immunity. Immune response evasion has been considered an important aspect of HPV persistence, which is the main contributing factor leading to HPV-related cancers. HPV-induced cancers expressing viral oncogenes E6 and E7 are potentially recognized by the immune system. The major histocompatibility complex (MHC) class I molecules are patrolled by natural killer cells and CD8+ cytotoxic T lymphocytes, respectively. This system of recognition is a main target for the strategies of immune evasion deployed by viruses. The viral immune evasion proteins constitute useful tools to block defined stages of the MHC class I presentation pathway, and in this way HPV avoids the host immune response. The long latency period from initial infection to persistence signifies that HPV evolves mechanisms to escape the immune response. It has now been established that there are oncogenic mechanisms by which E7 binds to and degrades tumor suppressor Rb, while E6 binds to and inactivates tumor suppressor p53. Therefore, interaction of p53 and pRb proteins can give rise to an increased immortalization and genomic instability. Overexpression of NF-κB in cervical and penile cancers suggests that NF-κB activation is a key modulator in driving chronic inflammation to cancer. HPV oncogene-mediated suppression of NF-κB activity contributes to HPV escape from the immune system. This review focuses on the diverse mechanisms of the virus immune evasion with HPV that leads to chronic inflammation and cancer.
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Affiliation(s)
- Masachika Senba
- Department of Pathology, Institute of Tropical Medicine, Nagasaki University
| | - Naoki Mori
- Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Japan
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29
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Abstract
Lampreys and hagfish are primitive jawless vertebrates capable of mounting specific immune responses. Lampreys possess different types of lymphocytes, akin to T and B cells of jawed vertebrates, that clonally express somatically diversified antigen receptors termed variable lymphocyte receptors (VLRs), which are composed of tandem arrays of leucine-rich repeats. The VLRs appear to be diversified by a gene conversion mechanism involving lineage-specific cytosine deaminases. VLRA is expressed on the surface of T-like lymphocytes; B-like lymphocytes express and secrete VLRB as a multivalent protein. VLRC is expressed by a distinct lymphocyte lineage. VLRA-expressing cells appear to develop in a thymus-like tissue at the tip of gill filaments, and VLRB-expressing cells develop in hematopoietic tissues. Reciprocal expression patterns of evolutionarily conserved interleukins and chemokines possibly underlie cell-cell interactions during an immune response. The discovery of VLRs in agnathans illuminates the origins of adaptive immunity in early vertebrates.
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Affiliation(s)
- Thomas Boehm
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Nathanael McCurley
- Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Yoichi Sutoh
- Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Michael Schorpp
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
| | - Masanori Kasahara
- Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
| | - Max D. Cooper
- Department of Pathology, Emory University School of Medicine, Atlanta, Georgia 30322
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30
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Moresco EMY, Beutler B. Resisting viral infection: the gene by gene approach. Curr Opin Virol 2011; 1:513-8. [PMID: 22440911 DOI: 10.1016/j.coviro.2011.10.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Revised: 10/05/2011] [Accepted: 10/07/2011] [Indexed: 01/18/2023]
Abstract
This review focuses on genes required for resistance to mouse cytomegalovirus (MCMV), as identified through unbiased genetic screening. Components of the developmental, sensing, and effector pathways, functioning in multiple cell types, were detected by infecting 22,000 G3 mutant mice with MCMV at an inoculum easily contained by WT animals. Merging these findings with discoveries from hypothesis-based studies, we present a cohesive picture of the essential elements utilized by the mouse innate immune system to counter MCMV. We believe that many breakthrough discoveries will yet be made using a classical genetic approach.
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Affiliation(s)
- Eva Marie Y Moresco
- Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037, USA
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31
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Kanwar N, Wilkins JA. IQGAP1 involvement in MTOC and granule polarization in NK-cell cytotoxicity. Eur J Immunol 2011; 41:2763-73. [PMID: 21681737 DOI: 10.1002/eji.201040444] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2010] [Revised: 04/30/2011] [Accepted: 06/10/2011] [Indexed: 11/06/2022]
Abstract
Natural killer (NK) cells form a region of tight contact called the NK immunological synapse (NKIS) with their target cells. This is a dynamic region serving as a platform for targeted signaling and exocytotic events. We previously identified IQGAP1 as a cytoskeletal component of the NK-like cell line YTS. The present study was undertaken to determine the role of IQGAP1 in the function of NK cells. Silencing of IQGAP1 expression resulted in almost complete loss of the cytotoxic activity of YTS cells. Loss of IQGAP1 did not prevent conjugate formation with target cells but it did result in a failure to reorient the microtubule organizing centre to the immune synapse. Significantly, IQGAP1 expression was required for the perigranular accumulation of an F-actin network. IQGAP1 was shown to undergo marked rearrangements during synapse maturation in effector target conjugates of YTS or primary NK cells. These results suggest previously undescribed role(s) for IQGAP1 in regulating multiple aspects of cytoskeletal organization and granule polarization in NK cells.
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Affiliation(s)
- Namita Kanwar
- Manitoba Centre for Proteomics and Systems Biology, Winnipeg, Manitoba, Canada.
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32
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De Vito P, Incerpi S, Pedersen JZ, Luly P, Davis FB, Davis PJ. Thyroid hormones as modulators of immune activities at the cellular level. Thyroid 2011; 21:879-90. [PMID: 21745103 DOI: 10.1089/thy.2010.0429] [Citation(s) in RCA: 230] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Increasing evidence suggests that thyroid hormones, L-thyroxine (T(4)) and 3,3',5-triiodo-L-thyronine (T(3)), are modulators of the immune response. In monocytes, macrophages, leukocytes, natural killer cells, and lymphocytes, a wide range of immune functions such as chemotaxis, phagocytosis, generation of reactive oxygen species (ROS), and cytokine synthesis and release are altered under hypo- and hyperthyroid conditions. SUMMARY Hyperthyroidism decreases the proinflammatory activities of monocytes and macrophages, whereas enhancement of phagocytosis and increased levels of ROS may occur during hypothyroidism. The expression of proinflammatory molecules such as macrophage inflammatory protein-1α and interleukin-1β increases in hypothyroidism. However, in Kupffer cells, proinflammatory activities such as the respiratory burst, nitric oxide synthase activity, and tumor necrosis factor-α expression may result from increased T(3) levels. Thyroid hormones also affect natural killer cell activity and cell-mediated immune responses. Still, for many immune cells no clear correlation has been found so far between abnormally high or low T(3) or T(4) levels and the effects observed on the immune responses. CONCLUSIONS In this review we outline the contributions of thyroid hormones to different aspects of innate and adaptive immune responses. The relationship between thyroid hormones and immune cells is complex and T(3) and T(4) may modulate immune responses through both genomic and nongenomic mechanisms. Future studies of the molecular signaling mechanisms involved in this cross-talk between thyroid hormones and the immune system may support development of new strategies to improve clinical immune responses.
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Affiliation(s)
- Paolo De Vito
- Department of Biology, University of Rome Tor Vergata, Rome, Italy.
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33
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The structural basis of ligand recognition by natural killer cell receptors. J Biomed Biotechnol 2011; 2011:203628. [PMID: 21629745 PMCID: PMC3100565 DOI: 10.1155/2011/203628] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2011] [Accepted: 03/14/2011] [Indexed: 11/18/2022] Open
Abstract
Natural killer cells are a group of lymphocytes which function as tightly controlled surveillance operatives which identify transformed cells through a discrete balance of activating and inhibitory receptors ultimately leading to the destruction of incongruent cells. The understanding of this finely tuned balancing act has been aided by the high-resolution structure determination of activating and inhibitory receptors both alone and in complex with their ligands. This paper collates these structural studies detailing the aspects which directly relate to the natural killer cell function and serves to inform both the specialized structural biologist reader and a more general immunology audience.
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34
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Abstract
The quest for an effective and safe HIV-1 vaccine has been and still is the aspiration of many scientists and clinicians worldwide. Until recently, the hopes for an effective vaccine were thwarted by the disappointing results and early termination in September 2007 of the STEP study, which saw a subgroup of male vaccine recipients at an increased risk of HIV-1 infection, and the failure of earlier trials of vaccines based on recombinant envelope proteins to provide any level of protection. The results of the STEP study raised important questions in the field of HIV vaccines, including the use of recombinant adenovirus vectors as immunogens, the rationale for the development of T-cell-based vaccines and the development pathway for these vaccines, in terms of assessment of immunogenicity and the challenge models used. The study of neutralizing antibodies has demonstrated that the induction of high-titre, broadly neutralizing antibodies in the majority of recipients is likely to be highly problematic. However, the results of the RV144 Thai trial released in September 2009 have brought new optimism to the field. This study employed envelope-based immunogens delivered as a priming vaccination with a recombinant poxvirus vector and boosting with recombinant proteins. This regimen provided modest protection to HIV-1 infection in a low-risk population. Although the correlates of protection are currently unknown, extensive studies are underway to try to determine these. Neutralizing antibodies were not induced in the RV144 study; however, considerable titres of binding antibodies to HIV-1 viral envelope (Env) were. It is speculated that these antibodies may have provided a means of protection by a mechanism such as antibody-dependent cell-mediated cytotoxicity. In addition, no CD8+ T-cell responses were induced, but robust CD4+ T-cell responses were, and correlates of protection are being sought by analysing the quality of this aspect of the vaccine-induced immune response. The current paradigm for an optimal HIV-1 vaccine is to design immunogens and vaccination protocols that allow the induction of both broadly neutralizing humoral and broadly reactive and effective cell-mediated immunity, to act at sites of possible infection and post-infection, respectively. However, this is challenged by the results of the RV144 trial as neither of these responses were induced but modest protection was observed. Understanding the biology and immunopathology of HIV-1 early following infection, its modes of transmission and the human immune system's response to the virus should aid in the rational design of vaccines of increased efficacy.
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Affiliation(s)
- C Mee Ling Munier
- HIV Immunovirology Laboratory, St Vincent's Centre for Applied Medical Research, Sydney, New South Wales, Australia.
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35
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Elpek KG, Rubinstein MP, Bellemare-Pelletier A, Goldrath AW, Turley SJ. Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Ralpha complexes. Proc Natl Acad Sci U S A 2010; 107:21647-52. [PMID: 21098276 PMCID: PMC3003106 DOI: 10.1073/pnas.1012128107] [Citation(s) in RCA: 98] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Cytotoxic lymphocytes such as natural killer (NK) and CD8 T cells play important roles in immunosurveillance by killing virally infected or malignant cells. The homeostatic cytokine, IL-15, promotes the development, function, and survival of NK and CD8 T cells. IL-15 is normally presented in trans as a surface complex with IL-15 receptor-alpha-chain (IL-15Rα) by dendritic cells (DCs) and monocytes. Signaling by IL-15 occurs via the IL-2/IL-15 receptor β-chain (CD122) which is expressed primarily by NK1.1(+) cells and CD8 T cells. The use of preformed complexes of IL-15 with soluble IL-15Rα complexes to boost the effector function of CD122(+) cytolytic lymphocytes such as NK and CD8 T cells has recently gained considerable attention. Here we describe the impact of transient and prolonged in vivo stimulation by IL-15/IL-15Rα complexes on NK and CD8 T cells. Whereas transitory stimulation increased the number of activated NK cells and significantly enhanced their effector function, prolonged stimulation by IL-15/IL-15Rα complexes led to a marked accumulation of mature NK cells with considerably impaired activation, cytotoxicity, and proliferative activity, and an altered balance of activating and inhibitory receptors. In contrast to NK cells, CD8 T cells exhibited an activated phenotype and robust T cell receptor stimulation and effector function upon chronic stimulation with IL-15/IL-15Rα complexes. Thus, prolonged stimulation with the strong activating signal leads to a preferential accrual of mature NK cells with altered activation and diminished functional capacity. These findings point to a negative feedback mechanism to preferentially counterbalance excessive NK cell activity and may have important implications for cytokine immunotherapy.
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Affiliation(s)
- Kutlu G. Elpek
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115
| | - Mark P. Rubinstein
- Division of Biology, University of California at San Diego, La Jolla, CA 92093; and
| | | | - Ananda W. Goldrath
- Division of Biology, University of California at San Diego, La Jolla, CA 92093; and
| | - Shannon J. Turley
- Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115
- Department of Pathology, Harvard Medical School, Boston, MA 02115
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36
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Flt3 permits survival during infection by rendering dendritic cells competent to activate NK cells. Proc Natl Acad Sci U S A 2010; 107:9759-64. [PMID: 20457904 DOI: 10.1073/pnas.1005186107] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
A previously unappreciated signal necessary for dendritic cell (DC)-mediated activation of natural killer (NK) cells during viral infection was revealed by a recessive N-ethyl-N-nitrosourea-induced mutation called warmflash (wmfl). Wmfl homozygotes displayed increased susceptibility to mouse cytomegalovirus (MCMV) infection. In response to MCMV infection in vivo, delayed NK cell activation was observed, but no intrinsic defects in NK cell activation or function were identified. Rather, coculture experiments demonstrated that NK cells are suboptimally activated by wmfl DCs, which showed impaired cytokine production in response to MCMV or synthetic TLR7 and TLR9 ligands. The wmfl mutation was identified in the gene encoding the Fms-like tyrosine kinase 3 (Flt3). Flt3 ligand (Flt3L) is transiently induced in the serum upon infection or TLR activation. However, antibody blockade reveals no acute requirement for Flt3L, suggesting that the Flt3L --> Flt3 axis programs the development of DCs, making them competent to support NK effector function. In the absence of Flt3 signaling, NK cell activation is delayed and survival during MCMV infection is markedly compromised.
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37
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Abstract
PURPOSE OF REVIEW Events occurring in acute HIV-1 infection are now recognized to be critical determinants of the subsequent disease course. Innate responses constitute the first line of defence against pathogens, and also play a key role in triggering the early adaptive response; as such, the innate responses activated in acute HIV-1 infection and their contribution to control of viral replication or disease pathogenesis are the focus of much current research. We review recent advances in this area. RECENT FINDINGS Dendritic cell subsets can play pleiotropic roles in acute HIV-1 infection, with in-vitro studies illustrating that HIV-dendritic cell interactions may have outcomes as diverse as virion destruction, virus dissemination, T-cell triggering or subversion of dendritic cell functions. Natural killer cells can be activated in acute HIV-1 infection, and mounting evidence suggests that they contribute to determining the ensuing course of disease; however, much remains to be learned about how they mediate their effects. SUMMARY The importance of innate responses as determinants of the outcome of HIV infection is increasingly evident, but more work is needed to understand how innate immunity can be harnessed to combat this infection.
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38
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Walshe VA, Hattotuwagama CK, Doytchinova IA, Wong M, Macdonald IK, Mulder A, Claas FHJ, Pellegrino P, Turner J, Williams I, Turnbull EL, Borrow P, Flower DR. Integrating in silico and in vitro analysis of peptide binding affinity to HLA-Cw*0102: a bioinformatic approach to the prediction of new epitopes. PLoS One 2009; 4:e8095. [PMID: 19956609 PMCID: PMC2779488 DOI: 10.1371/journal.pone.0008095] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2009] [Accepted: 11/03/2009] [Indexed: 11/24/2022] Open
Abstract
Background Predictive models of peptide-Major Histocompatibility Complex (MHC) binding affinity are important components of modern computational immunovaccinology. Here, we describe the development and deployment of a reliable peptide-binding prediction method for a previously poorly-characterized human MHC class I allele, HLA-Cw*0102. Methodology/Findings Using an in-house, flow cytometry-based MHC stabilization assay we generated novel peptide binding data, from which we derived a precise two-dimensional quantitative structure-activity relationship (2D-QSAR) binding model. This allowed us to explore the peptide specificity of HLA-Cw*0102 molecule in detail. We used this model to design peptides optimized for HLA-Cw*0102-binding. Experimental analysis showed these peptides to have high binding affinities for the HLA-Cw*0102 molecule. As a functional validation of our approach, we also predicted HLA-Cw*0102-binding peptides within the HIV-1 genome, identifying a set of potent binding peptides. The most affine of these binding peptides was subsequently determined to be an epitope recognized in a subset of HLA-Cw*0102-positive individuals chronically infected with HIV-1. Conclusions/Significance A functionally-validated in silico-in vitro approach to the reliable and efficient prediction of peptide binding to a previously uncharacterized human MHC allele HLA-Cw*0102 was developed. This technique is generally applicable to all T cell epitope identification problems in immunology and vaccinology.
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Affiliation(s)
- Valerie A. Walshe
- The Jenner Institute, University of Oxford, Compton, Berkshire, United Kingdom
| | | | | | - MaiLee Wong
- The Jenner Institute, University of Oxford, Compton, Berkshire, United Kingdom
| | - Isabel K. Macdonald
- The Jenner Institute, University of Oxford, Compton, Berkshire, United Kingdom
| | - Arend Mulder
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands
| | - Frans H. J. Claas
- Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Leiden, The Netherlands
| | - Pierre Pellegrino
- Centre for Sexual Health and HIV Research, Royal Free and University College London Medical School and Camden Primary Care Trust, London, United Kingdom
| | - Jo Turner
- Centre for Sexual Health and HIV Research, Royal Free and University College London Medical School and Camden Primary Care Trust, London, United Kingdom
| | - Ian Williams
- Centre for Sexual Health and HIV Research, Royal Free and University College London Medical School and Camden Primary Care Trust, London, United Kingdom
| | - Emma L. Turnbull
- The Jenner Institute, University of Oxford, Compton, Berkshire, United Kingdom
| | - Persephone Borrow
- The Jenner Institute, University of Oxford, Compton, Berkshire, United Kingdom
| | - Darren R. Flower
- The Jenner Institute, University of Oxford, Compton, Berkshire, United Kingdom
- * E-mail:
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39
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Protective and pathologic roles of the immune response to mouse hepatitis virus type 1: implications for severe acute respiratory syndrome. J Virol 2009; 83:9258-72. [PMID: 19570864 DOI: 10.1128/jvi.00355-09] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Intranasal mouse hepatitis virus type 1 (MHV-1) infection of mice induces lung pathology similar to that observed in severe acute respiratory syndrome (SARS) patients. However, the severity of MHV-1-induced pulmonary disease varies among mouse strains, and it has been suggested that differences in the host immune response might account for this variation. It has also been suggested that immunopathology may represent an important clinical feature of SARS. Little is known about the host immune response to MHV-1 and how it might contribute to some of the pathological changes detected in infected mice. In this study we show that an intact type I interferon system and the adaptive immune responses are required for controlling MHV-1 replication and preventing morbidity and mortality in resistant C57BL/6J mice after infection. The NK cell response also helps minimize the severity of illness following MHV-1 infection of C57BL/6J mice. In A/J and C3H/HeJ mice, which are highly susceptible to MHV-1-induced disease, we demonstrate that both CD4 and CD8 T cells contribute to morbidity during primary infection, and memory responses can enhance morbidity and mortality during subsequent reexposure to MHV-1. However, morbidity in A/J and C3H/HeJ mice can be minimized by treating them with immune serum prior to MHV-1 infection. Overall, our findings highlight the role of the host immune response in contributing to the pathogenesis of coronavirus-induced respiratory disease.
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40
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Kumar D, Hosse J, von Toerne C, Noessner E, Nelson PJ. JNK MAPK Pathway Regulates Constitutive Transcription of CCL5 by Human NK Cells through SP1. THE JOURNAL OF IMMUNOLOGY 2009; 182:1011-20. [DOI: 10.4049/jimmunol.182.2.1011] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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41
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Moldoveanu B, Otmishi P, Jani P, Walker J, Sarmiento X, Guardiola J, Saad M, Yu J. Inflammatory mechanisms in the lung. J Inflamm Res 2008. [PMID: 22096348 DOI: 10.2147/jir.s4385] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Inflammation is the body's response to insults, which include infection, trauma, and hypersensitivity. The inflammatory response is complex and involves a variety of mechanisms to defend against pathogens and repair tissue. In the lung, inflammation is usually caused by pathogens or by exposure to toxins, pollutants, irritants, and allergens. During inflammation, numerous types of inflammatory cells are activated. Each releases cytokines and mediators to modify activities of other inflammatory cells. Orchestration of these cells and molecules leads to progression of inflammation. Clinically, acute inflammation is seen in pneumonia and acute respiratory distress syndrome (ARDS), whereas chronic inflammation is represented by asthma and chronic obstructive pulmonary disease (COPD). Because the lung is a vital organ for gas exchange, excessive inflammation can be life threatening. Because the lung is constantly exposed to harmful pathogens, an immediate and intense defense action (mainly inflammation) is required to eliminate the invaders as early as possible. A delicate balance between inflammation and anti-inflammation is essential for lung homeostasis. A full understanding of the underlying mechanisms is vital in the treatment of patients with lung inflammation. This review focuses on cellular and molecular aspects of lung inflammation during acute and chronic inflammatory states.
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Affiliation(s)
- B Moldoveanu
- Department of Medicine, University of Louisville, Louisville, KY, USA, 40292
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Chaix J, Tessmer MS, Hoebe K, Fuséri N, Ryffel B, Dalod M, Alexopoulou L, Beutler B, Brossay L, Vivier E, Walzer T. Cutting edge: Priming of NK cells by IL-18. THE JOURNAL OF IMMUNOLOGY 2008; 181:1627-31. [PMID: 18641298 DOI: 10.4049/jimmunol.181.3.1627] [Citation(s) in RCA: 243] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Recent evidence suggests that NK cells require priming to display full effector activity. In this study, we demonstrate that IL-18 contributed to this phenomenon. IL-18 signaling-deficient NK cells were found to be unable to secrete IFN-gamma in response to ex vivo stimulation with IL-12. This was not due to a costimulatory role of IL-18, because blocking IL-18 signaling during the ex vivo stimulation with IL-12 did not alter IFN-gamma production by wild-type NK cells. Rather, we demonstrate that IL-18 primes NK cells in vivo to produce IFN-gamma upon subsequent stimulation with IL-12. Importantly, IL-12-induced IFN-gamma transcription by NK cells was comparable in IL-18 signaling-deficient and -sufficient NK cells. This suggests that priming by IL-18 leads to an improved translation of IFN-gamma mRNA. These results reveal a novel type of cooperation between IL-12 and IL-18 that requires the sequential action of these cytokines.
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Affiliation(s)
- Julie Chaix
- Centre d'Immunologie de Marseille-Luminy, Université de la Méditerranée, Institut National de la Santé et de la Recherche Médicale Unité, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6102, Marseille, France
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Extrinsic and intrinsic regulation of early natural killer cell development. Immunol Res 2008; 40:193-207. [PMID: 18266115 DOI: 10.1007/s12026-007-8006-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Natural killer (NK) cells are lymphocytes that play a critical role in both adaptive and innate immune responses. These cells develop from multipotent progenitors in the embryonic thymus and neonatal or adult bone marrow and recent evidence suggests that a subset of these cells may develop in the thymus. Thymus- and bone marrow-derived NK cells have unique phenotypes and functional abilities supporting the hypothesis that the microenvironment dictates the outcome of NK cell development. A detailed understanding of the mechanisms controlling this developmental program will be required to determine how alterations in NK cell development lead to disease and to determine how to harness this developmental program for therapeutic purposes. In this review, we discuss some of the known extrinsic stromal-cell derived factors and cell intrinsic transcription factors that function in guiding NK cell development.
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Natural killer cells in peripheral blood and lung tissue are associated with chronic rejection after lung transplantation. J Heart Lung Transplant 2008; 27:203-7. [PMID: 18267228 DOI: 10.1016/j.healun.2007.11.571] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2007] [Revised: 10/08/2007] [Accepted: 11/26/2007] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Natural killer (NK) cells have the capacity to recognize and respond to alloantigen, yet their role in lung transplant rejection is not well defined. The aim of this study was to correlate NK cell numbers and immunophenotype in peripheral blood and tissue with graft function after lung transplantation. METHODS NK cell subsets were immunophenotyped in peripheral blood (n = 41). Lung tissue was stained for NK cells via CD16 and morphologic assessment (n = 30). RESULTS Peripheral blood NK cells were activated in patients with chronic rejection, but the overall number of cells was lower in these patients when compared with stable patients. Furthermore, there was significantly more CD16(+) NK cells in the lung compartment of patients with bronchiolitis obliterans syndrome compared with stable patients (p = 0.001). CONCLUSIONS In patients with chronic rejection, peripheral blood NK cells are activated but their numbers decrease, while the number of NK cells in the lungs increases. This suggests NK cells systemically activate and migrate to the lung during the progression of chronic rejection after lung transplantation.
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A role for interleukin-12/23 in the maturation of human natural killer and CD56+ T cells in vivo. Blood 2008; 111:5008-16. [PMID: 18319400 DOI: 10.1182/blood-2007-11-122259] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Natural killer (NK) cells have been originally defined by their "naturally occurring" effector function. However, only a fraction of human NK cells is reactive toward a panel of prototypical tumor cell targets in vitro, both for the production of interferon-gamma (IFN-gamma) and for their cytotoxic response. In patients with IL12RB1 mutations that lead to a complete IL-12Rbeta1 deficiency, the size of this naturally reactive NK cell subset is diminished, in particular for the IFN-gamma production. Similar data were obtained from a patient with a complete deficit in IL-12p40. In addition, the size of the subset of effector memory T cells expressing CD56 was severely decreased in IL-12Rbeta1- and IL-12p40-deficient patients. Human NK cells thus require in vivo priming with IL-12/23 to acquire their full spectrum of functional reactivity, while T cells are dependent upon IL-12/23 signals for the differentiation and/or the maintenance of CD56(+) effector memory T cells. The susceptibility of IL-12/23 axis-deficient patients to Mycobacterium and Salmonella infections in combination with the absence of mycobacteriosis or salmonellosis in the rare cases of human NK cell deficiencies point to a role for CD56(+) T cells in the control of these infections in humans.
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46
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Natural killer cells and alterations in collagen density: signs of periradicular herpesvirus infection? Clin Oral Investig 2007; 12:129-35. [DOI: 10.1007/s00784-007-0165-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2007] [Accepted: 11/05/2007] [Indexed: 11/26/2022]
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Guan H, Moretto M, Bzik DJ, Gigley J, Khan IA. NK cells enhance dendritic cell response against parasite antigens via NKG2D pathway. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2007; 179:590-6. [PMID: 17579080 DOI: 10.4049/jimmunol.179.1.590] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Recent studies have shown that NK-dendritic cell (DC) interaction plays an important role in the induction of immune response against tumors and certain viruses. Although the effect of this interaction is bidirectional, the mechanism or molecules involved in this cross-talk have not been identified. In this study, we report that coculture with NK cells causes several fold increase in IL-12 production by Toxoplasma gondii lysate Ag-pulsed DC. This interaction also leads to stronger priming of Ag-specific CD8+ T cell response by these cells. In vitro blockade of NKG2D, a molecule present on human and murine NK cells, neutralizes the NK cell-induced up-regulation of DC response. Moreover, treatment of infected animals with Ab to NKG2D receptor compromises the development of Ag-specific CD8+ T cell immunity and reduces their ability to clear parasites. These studies emphasize the critical role played by NKG2D in the NK-DC interaction, which apparently is important for the generation of robust CD8+ T cell immunity against intracellular pathogens. To the best of our knowledge, this is the first work that describes in vivo importance of NKG2D during natural infection.
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Affiliation(s)
- Hongbing Guan
- Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
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Abstract
Bone marrow transplants are an important therapeutic tool for treating certain types of cancer as well as genetic diseases affecting the hematopoietic system. Until the transferred stem cells differentiate and reconstitute the immune system, recipients are at increased risk from opportunistic infections. We report the rapid generation of a functional natural killer (NK) compartment in lethally irradiated mice that received bone marrow cells from a syngeneic donor by treatment with IL-2/anti-IL-2 antibody complexes. We demonstrate that IL-2 complexes specifically expand the donor but not the host NK population and discuss the implications of this finding in the context of graft-versus-host disease and tumor relapse. Finally, we show that NK cells rapidly generated by IL-2 complexes kill MHC class I-deficient cells effectively in vivo. These data underline the unique therapeutic potential of IL-2 complexes.
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Affiliation(s)
- Martin Prlic
- Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle , WA 98195-7370, USA
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Jabri B, Ebert E. Human CD8+intraepithelial lymphocytes: a unique model to study the regulation of effector cytotoxic T lymphocytes in tissue. Immunol Rev 2007; 215:202-14. [PMID: 17291290 DOI: 10.1111/j.1600-065x.2006.00481.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The epithelium of the human small intestine contains a large population of intraepithelial cytolytic alphabeta T-cell receptor (TCR) CD8 alpha beta T lymphocytes (IE-CTLs), whose main role is to sustain epithelial integrity by rapidly eliminating infected and damaged cells. In mouse, the recognition of inducible/modified self-molecules, i.e. non-classical major histocompatibility complex (MHC) class I molecules, is mediated by the TCR and natural killer receptors (NKRs) co-expressed on the cell surface of a non-conventional autoreactive CD8 alpha alpha alpha beta TCR cell subset. In contrast, in humans, the recognition of non-classical MHC class I molecules induced by stress and inflammation on intestinal epithelial cells (IECs) is principally mediated by NKRs expressed on conventional CD8 alpha beta alpha beta TCR cells. By sensing microenvironmental signals of inflammation and stress through NKRs, IE-CTLs fine tune their TCR activation threshold. Furthermore, IE-CTLs under particular conditions, involving interleukin-15 upregulation, acquire the capacity to kill distressed intestinal epithelial cells in an antigen non-specific manner. Adaptive IE-CTLs appear hence to have autoreactive properties and modulate their immune response based on innate signals, reflecting the fitness of the tissue.
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Affiliation(s)
- Bana Jabri
- Department of Pathology, Medicine and Pediatrics, University of Chicago, Chicago, IL 60637, USA.
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Abstract
Multicellular organisms possess very sophisticated defense mechanisms that are designed to effectively counter the continual microbial insult of the environment within the vertebrate host. However, successful microbial pathogens have in turn evolved complex and efficient methods to overcome innate and adaptive immune mechanisms, which can result in disease or chronic infections. Although the various virulence strategies used by viral and bacterial pathogens are numerous, there are several general mechanisms that are used to subvert and exploit immune systems that are shared between these diverse microbial pathogens. The success of each pathogen is directly dependant on its ability to mount an effective anti-immune response within the infected host, which can ultimately result in acute disease, chronic infection, or pathogen clearance. In this review, we highlight and compare some of the many molecular mechanisms that bacterial and viral pathogens use to evade host immune defenses.
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Affiliation(s)
- B Brett Finlay
- Michael Smith Laboratories, University of British Columbia, Vancouver, B.C. V6T 1Z4 Canada.
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