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Li S, Zhang J, Wei W, Zhang Z, Huang W, Xia L. The important role of myeloid-derived suppressor cells: From hepatitis to liver cancer. Biochim Biophys Acta Rev Cancer 2025; 1880:189329. [PMID: 40262654 DOI: 10.1016/j.bbcan.2025.189329] [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: 09/26/2024] [Revised: 04/15/2025] [Accepted: 04/15/2025] [Indexed: 04/24/2025]
Abstract
Liver homeostasis is coordinated by crosstalk between resident and infiltrating inflammatory cells. Liver disease creates a dynamic inflammatory microenvironment characterized by aberrant metabolism and continuous hepatic regeneration, making it an important risk factor for hepatocellular carcinoma (HCC) as well as liver failure. Recent studies have revealed a critical heterogeneous population of myeloid-derived suppressor cells (MDSCs), which influence liver disease progression and malignancy by dynamically regulating the immune microenvironment. MDSCs play an important role in preventing excessive immune responses in the liver. However, MDSCs are also associated with the promotion of liver injury and liver cancer progression. The plasticity of MDSCs in liver disease is a unique challenge for therapeutic intervention strategies and requires a deeper understanding of the underlying mechanisms. Here, we review the role of MDSCs in the establishment and progression of liver disease and highlight the evidence for MDSCs as a priority target for current and future therapeutic strategies. We explore the fate of MDSCs from hepatitis to liver cancer, providing recent insights into potential targets for clinical intervention.
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Affiliation(s)
- Siwen Li
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Jiaqian Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wang Wei
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Zhicheng Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
| | - Wenjie Huang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei 430030, China.
| | - Limin Xia
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
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Zhan C, Peng C, Wei H, Wei K, Ou Y, Zhang Z. Diverse Subsets of γδT Cells and Their Specific Functions Across Liver Diseases. Int J Mol Sci 2025; 26:2778. [PMID: 40141420 PMCID: PMC11943347 DOI: 10.3390/ijms26062778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Revised: 03/15/2025] [Accepted: 03/17/2025] [Indexed: 03/28/2025] Open
Abstract
γδT cells, a distinct group of T lymphocytes, serve as a link between innate and adaptive immune responses. They are pivotal in the pathogenesis of various liver disorders, such as viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), liver fibrosis, autoimmune liver diseases, and hepatocellular carcinoma (HCC). Despite their importance, the functional diversity and regulatory mechanisms of γδT cells remain incompletely understood. Recent advances in high-throughput single-cell sequencing and spatial transcriptomics have revealed significant heterogeneity among γδT cell subsets, particularly Vδ1+ and Vδ2+, which exhibit distinct immunological roles. Vδ1+ T cells are mainly tissue-resident and contribute to tumor immunity and chronic inflammation, while Vδ2+ T cells, predominantly found in peripheral blood, play roles in systemic immune surveillance but may undergo dysfunction in chronic liver diseases. Additionally, γδT17 cells exacerbate inflammation in NAFLD and ALD, whereas IFN-γ-secreting γδT cells contribute to antiviral and antifibrotic responses. These discoveries have laid the foundation for the creation of innovative solutions. γδT cell-based immunotherapeutic approaches, such as adoptive cell transfer, immune checkpoint inhibition, and strategies targeting metabolic pathways. Future research should focus on harnessing γδT cells' therapeutic potential through targeted interventions, offering promising prospects for precision immunotherapy in liver diseases.
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Affiliation(s)
- Chenjie Zhan
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
| | - Chunxiu Peng
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
| | - Huaxiu Wei
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
| | - Ke Wei
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
| | - Yangzhi Ou
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
| | - Zhiyong Zhang
- State Key Laboratory of Targeting Oncology, National Center for International Research of Bio-Targeting Theranostics, Guangxi Key Laboratory of Bio-Targeting Theranostics, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Talent Highland of Major New Drugs Innovation and Development, Guangxi Medical University, Nanning 530021, China; (C.Z.); (C.P.)
- Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, New Brunswick, NJ 08901-8554, USA
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Coronado L, Wang M, Bohórquez JA, Muñoz-Aguilera A, Alberch M, Martínez P, Ruggli N, Ramayo-Caldas Y, Ganges L. Gene Expression Signatures of Porcine Bone Marrow-Derived Antigen-Presenting Cells Infected with Classical Swine Fever Virus. Viruses 2025; 17:160. [PMID: 40006915 PMCID: PMC11860178 DOI: 10.3390/v17020160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 01/15/2025] [Accepted: 01/16/2025] [Indexed: 02/27/2025] Open
Abstract
For a better understanding of classical swine fever (CSF) pathogenesis, a transcriptomic analysis was performed using porcine bone marrow (BM)-derived antigen-presenting cells (APCs) infected ex vivo with two different cDNA-derived classical swine fever virus (CSFV) strains, the low-virulence Pinar de Rio (vPdR-36U) or the lethal vPdR-H30K-5U. The transcriptomic profile of vPdR-36U- or vPdR-H30K-5U-infected versus noninfected cells revealed 946 and 2643 differentially expressed genes (DEGs), respectively. The upregulation of ISG15, CXCL-10, ADAM8, and CSF1 was found after infection with vPdR-36U, which could contribute to the generation of mild CSF forms. In contrast, cells infected with the lethal vPdR-H30K-5U overexpressed the immune checkpoint molecules PD-L1, CD276, and LAG3, which are involved in T-cell exhaustion and could be associated with adaptive immunity impairment. vPdR-H30K-5U also induced increased expression of PPBP, IL-8, IL-6, ECE1, and Rab27b, which are mediators of inflammatory responses that can be involved in cytokine storms. The TNF signaling pathway, which is related to the activation and proliferation of different subsets of immune cells, including CD4+ T cells, was notably upregulated in response to the low-pathogenicity virus. The Th17, Th1, and Th2 differentiation pathways were downregulated by the highly pathogenic virus only, supporting the role of T-cell-mediated immunity in protecting against CSFV.
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Affiliation(s)
- Liani Coronado
- Institute for Research and Technology in Food and Agriculture (IRTA), Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain; (L.C.); (M.W.); (J.A.B.); (A.M.-A.); (M.A.); (P.M.)
- Unitat Mixta d’Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain
- Classical Swine Fever World Organization for Animal Health (WOAH) Reference Laboratory for, IRTA-CReSA, 08193 Barcelona, Spain
| | - Miaomiao Wang
- Institute for Research and Technology in Food and Agriculture (IRTA), Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain; (L.C.); (M.W.); (J.A.B.); (A.M.-A.); (M.A.); (P.M.)
- Unitat Mixta d’Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain
- Classical Swine Fever World Organization for Animal Health (WOAH) Reference Laboratory for, IRTA-CReSA, 08193 Barcelona, Spain
| | - Jose Alejandro Bohórquez
- Institute for Research and Technology in Food and Agriculture (IRTA), Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain; (L.C.); (M.W.); (J.A.B.); (A.M.-A.); (M.A.); (P.M.)
- Unitat Mixta d’Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain
- Classical Swine Fever World Organization for Animal Health (WOAH) Reference Laboratory for, IRTA-CReSA, 08193 Barcelona, Spain
| | - Adriana Muñoz-Aguilera
- Institute for Research and Technology in Food and Agriculture (IRTA), Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain; (L.C.); (M.W.); (J.A.B.); (A.M.-A.); (M.A.); (P.M.)
- Unitat Mixta d’Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain
- Classical Swine Fever World Organization for Animal Health (WOAH) Reference Laboratory for, IRTA-CReSA, 08193 Barcelona, Spain
- Instituto Colombiano Agropecuario (ICA), Bogotá 110911, Colombia
| | - Mònica Alberch
- Institute for Research and Technology in Food and Agriculture (IRTA), Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain; (L.C.); (M.W.); (J.A.B.); (A.M.-A.); (M.A.); (P.M.)
- Unitat Mixta d’Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain
- Classical Swine Fever World Organization for Animal Health (WOAH) Reference Laboratory for, IRTA-CReSA, 08193 Barcelona, Spain
| | - Patricia Martínez
- Institute for Research and Technology in Food and Agriculture (IRTA), Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain; (L.C.); (M.W.); (J.A.B.); (A.M.-A.); (M.A.); (P.M.)
- Unitat Mixta d’Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain
- Classical Swine Fever World Organization for Animal Health (WOAH) Reference Laboratory for, IRTA-CReSA, 08193 Barcelona, Spain
| | - Nicolas Ruggli
- Division of Virology, Institute of Virology and Immunology (IVI), 3147 Mittelhäusern, Switzerland;
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland
| | - Yuliaxis Ramayo-Caldas
- Animal Breeding and Genetics Program, Institute for Research and Technology in Food and Agriculture (IRTA), Torre Marimon, 08140 Caldes de Montbui, Spain;
| | - Llilianne Ganges
- Institute for Research and Technology in Food and Agriculture (IRTA), Programa de Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain; (L.C.); (M.W.); (J.A.B.); (A.M.-A.); (M.A.); (P.M.)
- Unitat Mixta d’Investigació IRTA-UAB en Sanitat Animal, Centre de Recerca en Sanitat Animal (CReSA), Bellaterra, 08193 Barcelona, Spain
- Classical Swine Fever World Organization for Animal Health (WOAH) Reference Laboratory for, IRTA-CReSA, 08193 Barcelona, Spain
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Guan Q, Gilpin SG, Doerksen J, Bath L, Lam T, Li Y, Lambert P, Wall DA. The Interactions of T Cells with Myeloid-Derived Suppressor Cells in Peripheral Blood Stem Cell Grafts. Cells 2024; 13:1545. [PMID: 39329729 PMCID: PMC11429538 DOI: 10.3390/cells13181545] [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: 08/06/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 09/28/2024] Open
Abstract
The interaction of myeloid-derived suppressor cells (MDSCs) with T cells within G-CSF-mobilized peripheral blood stem cell (PBSC) grafts in patients undergoing autologous or allogeneic hematopoietic stem cell transplantation remains to be elucidated. Through studying allo- and auto-PBSC grafts, we observed grafts containing large numbers of T cells and MDSCs with intergraft variability in their percentage and number. T cells from autologous grafts compared to allografts expressed relative higher percentages of inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, TIGIT and BTLA. Autograft T cells had decreased cell proliferation and IFN-γ secretion, which supported the possible presence of T cell exhaustion. On the contrary, graft monocytic MDSCs (M-MDSCs) expressed multiple inhibitory receptor ligands, including PD-L1, CD86, Galectin-9, HVEM and CD155. The expression of inhibitory receptor ligands on M-MDSCs was correlated with their corresponding inhibitory receptors on T cells in the grafts. Isolated M-MDSCs had the ability to suppress T cell proliferation and IFN-γ secretion and/or promote Treg expansion. Blocking the PD-L1-PD-1 signaling pathway partially reversed the functions of M-MDSCs. Taken together, our data indicated that T cells and M-MDSCs in PBSC grafts express complementary inhibitory receptor-ligand pairing, which may impact the quality of immune recovery and clinical outcome post transplantation.
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Affiliation(s)
- Qingdong Guan
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
- Department of Immunology, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- Manitoba Center for Advanced Cell and Tissue Therapy, Winnipeg, MB R3A 1R9, Canada
- Paul Albreachtsen Research Institute, CancerCare Manitoba, Winnipeg, MB R3A 1R9, Canada
| | - Scott G. Gilpin
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - James Doerksen
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Lauren Bath
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Tracy Lam
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Yun Li
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Pascal Lambert
- Department of Epidemiology and Cancer Registry, CancerCare Manitoba, Winnipeg, MB R3A 1R9, Canada;
| | - Donna A. Wall
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
- Department of Immunology, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- Manitoba Center for Advanced Cell and Tissue Therapy, Winnipeg, MB R3A 1R9, Canada
- Paul Albreachtsen Research Institute, CancerCare Manitoba, Winnipeg, MB R3A 1R9, Canada
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Yang AYP, Wistuba-Hamprecht K, Greten TF, Ruf B. Innate-like T cells in liver disease. Trends Immunol 2024; 45:535-548. [PMID: 38879436 DOI: 10.1016/j.it.2024.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2024] [Revised: 05/27/2024] [Accepted: 05/27/2024] [Indexed: 07/14/2024]
Abstract
Mammalian innate-like T cells (ILTCs), including mucosal-associated invariant T (MAIT), natural killer T (NKT), and γδ T cells, are abundant tissue-resident lymphocytes that have recently emerged as orchestrators of hepatic inflammation, tissue repair, and immune homeostasis. This review explores the involvement of different ILTC subsets in liver diseases. We explore the mechanisms underlying the pro- and anti-inflammatory effector functions of ILTCs in a context-dependent manner. We highlight latest findings regarding the dynamic interplay between ILTC functional subsets and other immune and parenchymal cells which may inform candidate immunomodulatory strategies to achieve improved clinical outcomes in liver diseases. We present new insights into how distinct gene expression programs in hepatic ILTCs are induced, maintained, and reprogrammed in a context- and disease stage-dependent manner.
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Affiliation(s)
- Albert Ying-Po Yang
- Department of Internal Medicine I, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany; M3 Research Center for Malignome, Metabolome, and Microbiome, Faculty of Medicine, University of Tübingen, Tübingen, Germany
| | - Kilian Wistuba-Hamprecht
- Department of Internal Medicine I, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany; M3 Research Center for Malignome, Metabolome, and Microbiome, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) - Image-Guided and Functionally Instructed Tumor Therapies, University of Tübingen, Tübingen, Germany; Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Dermatology, Venereology, and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Center for Cancer Research (CCR) Liver Cancer Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Benjamin Ruf
- Department of Internal Medicine I, University Hospital Tübingen, Eberhard Karls University of Tübingen, Tübingen, Germany; M3 Research Center for Malignome, Metabolome, and Microbiome, Faculty of Medicine, University of Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) - Image-Guided and Functionally Instructed Tumor Therapies, University of Tübingen, Tübingen, Germany.
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Xie H, Deng H, Yang X, Gao X, Yang S, Chen W, Wang Y, Yang N, Yong L, Hou X. Mesencephalic Astrocyte-derived Neurotrophic Factor Supports Hepatitis B Virus-induced Immunotolerance. Cell Mol Gastroenterol Hepatol 2024; 18:101360. [PMID: 38759839 PMCID: PMC11255368 DOI: 10.1016/j.jcmgh.2024.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 05/10/2024] [Accepted: 05/10/2024] [Indexed: 05/19/2024]
Abstract
BACKGROUND & AIMS The immune tolerance induced by hepatitis B virus (HBV) is a major challenge for achieving effective viral clearance, and the mechanisms involved are not well-understood. One potential factor involved in modulating immune responses is mesencephalic astrocyte-derived neurotrophic factor (MANF), which has been reported to be increased in patients with chronic hepatitis B. In this study, our objective is to examine the role of MANF in regulating immune responses to HBV. METHODS We utilized a commonly used HBV-harboring mouse model, where mice were hydrodynamically injected with the pAAV/HBV1.2 plasmid. We assessed the HBV load by measuring the levels of various markers including hepatitis B surface antigen, hepatitis B envelope antigen, hepatitis B core antigen, HBV DNA, and HBV RNA. RESULTS Our study revealed that following HBV infection, both myeloid cells and hepatocytes exhibited increased expression of MANF. Moreover, we observed that mice with myeloid-specific MANF knockout (ManfMye-/-) displayed reduced HBV load and improved HBV-specific T cell responses. The decreased HBV-induced tolerance in ManfMye-/- mice was associated with reduced accumulation of myeloid-derived suppressor cells (MDSCs) in the liver. Restoring MDSC levels in ManfMye-/- mice through MDSC adoptive transfer reinstated HBV-induced tolerance. Mechanistically, we found that MANF promoted MDSC expansion by activating the IL-6/STAT3 pathway. Importantly, our study demonstrated the effectiveness of a combination therapy involving an hepatitis B surface antigen vaccine and nanoparticle-encapsulated MANF siRNA in effectively clearing HBV in HBV-carrier mice. CONCLUSION The current study reveals that MANF plays a previously unrecognized regulatory role in liver tolerance by expanding MDSCs in the liver through IL-6/STAT3 signaling, leading to MDSC-mediated CD8+ T cell exhaustion.
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Affiliation(s)
- Huiyuan Xie
- Department of Laboratory Medicine, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Haiyan Deng
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Xiaoping Yang
- Department of Hepatopancreatobiliary Surgery, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Xianxian Gao
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Shanru Yang
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Weiyi Chen
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Yixuan Wang
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Naibin Yang
- Department of Infection, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Liang Yong
- Laboratory of Stem Cell, the First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, P. R. China
| | - Xin Hou
- Health Science Center, Ningbo University, Ningbo, Zhejiang, P. R. China.
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7
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Kesse S, Xu Y, Shi S, Jin S, Ullah S, Dai Y, He M, Zheng A, Xu F, Du Z, Alolga RN, Peng J. MDSC-targeted liposomal all-trans retinoic acid suppresses mMdscs and improves immunotherapy in HBV infection. Expert Opin Drug Deliv 2024; 21:347-363. [PMID: 38406829 DOI: 10.1080/17425247.2024.2317936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2023] [Accepted: 02/08/2024] [Indexed: 02/27/2024]
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) are evolving as a prominent determinant in cancer occurrence and development and are functionally found to suppress T cells in cancer. Not much research is done regarding its involvement in viral infections. This research was designed to investigate the role of MDSCs in hepatitis B virus (HBV) infection and how targeting these cells with our novel all-trans retinoic acid encapsulated liposomal formulation could improve immunotherapy in C57BL/6 mice. METHODS Ten micrograms (10 μg) of plasmid adeno-associated virus (pAAV/HBV 1.2, genotype A) was injected hydrodynamically via the tail vein of C57BL/6 mice. An all-trans retinoic acid encapsulated liposomal formulation (L-ATRA) with sustained release properties was used in combination with tenofovir disoproxil fumarate (TDF), a nucleotide analog reverse transcriptase inhibitor (nRTI) to treat the HBV infection. The L-ATRA formulation was given at a dose of 5 mg/kg intravenously (IV) twice a week. The TDF was given orally at 30 mg/kg daily. RESULTS Our results revealed that L-ATRA suppresses MDSCs in HBV infected mice and enhanced T-cell proliferation in vitro. In vivo studies showed higher and improved immunotherapeutic effect in mice that received L-ATRA and TDF concurrently in comparison with the groups that received monotherapy. Lower HBV DNA copies, lower concentrations of HBsAg and HBeAg, lower levels of ALT and AST and less liver damage were seen in the mice that received the combination therapy of L-ATRA + TDF. CONCLUSIONS In effect, targeting MDSCs with the combination of L-ATRA and TDF effectively reduced mMDSC and improved immunotherapy in the HBV infected mice. Targeting MDSCs could provide a breakthrough in the fight against hepatitis B virus infection.
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Affiliation(s)
- Samuel Kesse
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Yuhong Xu
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- Yunnan Key Laboratory of Screening and Research on Anti-pathogen Plant Resources in Western Yunnan, Dali University, Dali, China
- HighField Biopharmaceuticals Inc, Hangzhou, China
| | - Sanyuan Shi
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Shanshan Jin
- HighField Biopharmaceuticals Inc, Hangzhou, China
| | - Shafi Ullah
- Shanghai Institute of Digestive Diseases, Renji Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yongchao Dai
- HighField Biopharmaceuticals Inc, Hangzhou, China
| | - Miao He
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- Yunnan Key Laboratory of Screening and Research on Anti-pathogen Plant Resources in Western Yunnan, Dali University, Dali, China
| | - Anjie Zheng
- HighField Biopharmaceuticals Inc, Hangzhou, China
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Fengwei Xu
- HighField Biopharmaceuticals Inc, Hangzhou, China
| | - Zixiu Du
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Raphael N Alolga
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jinliang Peng
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
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Ju T, Jiang D, Zhong C, Zhang H, Huang Y, Zhu C, Yang S, Yan D. Characteristics of circulating immune cells in HBV-related acute-on-chronic liver failure following artificial liver treatment. BMC Immunol 2023; 24:47. [PMID: 38007423 PMCID: PMC10676598 DOI: 10.1186/s12865-023-00579-8] [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: 07/18/2023] [Accepted: 10/19/2023] [Indexed: 11/27/2023] Open
Abstract
BACKGROUND AND AIM Liver failure, which is predominantly caused by hepatitis B (HBV) can be improved by an artificial liver support system (ALSS). This study investigated the phenotypic heterogeneity of immunocytes in patients with HBV-related acute-on-chronic liver failure (HBV-ACLF) before and after ALSS therapy. METHODS A total of 22 patients with HBV-ACLF who received ALSS therapy were included in the study. Patients with Grade I according to the ACLF Research Consortium score were considered to have improved. Demographic and laboratory data were collected and analyzed during hospitalization. Immunological features of peripheral blood in the patients before and after ALSS were detected by mass cytometry analyses. RESULTS In total, 12 patients improved and 10 patients did not. According to the immunological features data after ALSS, the proportion of circulating monocytes was significantly higher in non-improved patients, but there were fewer γδT cells compared with those in improved patients. Characterization of 37 cell clusters revealed that the frequency of effector CD8+ T (P = 0.003), CD4+ TCM (P = 0.033), CD4+ TEM (P = 0.039), and inhibitory natural killer (NK) cells (P = 0.029) decreased in HBV-ACLF patients after ALSS therapy. Sub group analyses after treatment showed that the improved patients had higher proportions of CD4+ TCM (P = 0.010), CD4+ TEM (P = 0.021), and γδT cells (P = 0.003) and a lower proportion of monocytes (P = 0.012) compared with the non-improved patients. CONCLUSIONS Changes in effector CD8+ T cells, effector and memory CD4+ T cells, and inhibitory NK cells are associated with ALSS treatment of HBV-ACLF. Moreover, monocytes and γδT cells exhibited the main differences when patients obtained different prognoses. The phenotypic heterogeneity of lymphocytes and monocytes may contribute to the prognosis of ALSS and future immunotherapy strategies.
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Affiliation(s)
- Tao Ju
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Daixi Jiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Chengli Zhong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Huafen Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Yandi Huang
- Department of Laboratory Medicine, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310003, China
| | - Chunxia Zhu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China
| | - Shigui Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.
| | - Dong Yan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.
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9
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Koh CH, Lee S, Kwak M, Kim BS, Chung Y. CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential. Exp Mol Med 2023; 55:2287-2299. [PMID: 37907738 PMCID: PMC10689838 DOI: 10.1038/s12276-023-01105-x] [Citation(s) in RCA: 92] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/11/2023] [Accepted: 08/12/2023] [Indexed: 11/02/2023] Open
Abstract
CD8 T cells play crucial roles in immune surveillance and defense against infections and cancer. After encountering antigenic stimulation, naïve CD8 T cells differentiate and acquire effector functions, enabling them to eliminate infected or malignant cells. Traditionally, cytotoxic T cells, characterized by their ability to produce effector cytokines and release cytotoxic granules to directly kill target cells, have been recognized as the constituents of the predominant effector T-cell subset. However, emerging evidence suggests distinct subsets of effector CD8 T cells that each exhibit unique effector functions and therapeutic potential. This review highlights recent advancements in our understanding of CD8 T-cell subsets and the contributions of these cells to various disease pathologies. Understanding the diverse roles and functions of effector CD8 T-cell subsets is crucial to discern the complex dynamics of immune responses in different disease settings. Furthermore, the development of immunotherapeutic approaches that specifically target and regulate the function of distinct CD8 T-cell subsets holds great promise for precision medicine.
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Affiliation(s)
- Choong-Hyun Koh
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Suyoung Lee
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Minkyeong Kwak
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Byung-Seok Kim
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
- Wide River Institute of Immunology, Seoul National University, Hongcheon, Gangwon, 25159, Republic of Korea.
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10
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Ablikim D, Zeng X, Xu C, Zhao M, Yang X, Feng X, Liu J. The Multiple Facets and Disorders of B Cell Functions in Hepatitis B Virus Infection. J Clin Med 2023; 12:jcm12052000. [PMID: 36902786 PMCID: PMC10004556 DOI: 10.3390/jcm12052000] [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: 01/27/2023] [Revised: 02/28/2023] [Accepted: 03/01/2023] [Indexed: 03/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a global public health burden. B cells play a pivotal role in mediating HBV clearance and can participate in the development of anti-HBV adaptive immune responses through multiple mechanisms, such as antibody production, antigen presentation, and immune regulation. However, B cell phenotypic and functional disorders are frequently observed during chronic HBV infection, suggesting the necessity of targeting the disordered anti-HBV B cell responses to design and test new immune therapeutic strategies for the treatment of chronic HBV infection. In this review, we provide a comprehensive summary of the multiple roles of B cells in mediating HBV clearance and pathogenesis as well as the latest developments in understanding the immune dysfunction of B cells in chronic HBV infection. Additionally, we discuss novel immune therapeutic strategies that aim to enhance anti-HBV B cell responses for curing chronic HBV infection.
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Affiliation(s)
- Dilhumare Ablikim
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaoqing Zeng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chunli Xu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Mengxiao Zhao
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xuecheng Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xuemei Feng
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jia Liu
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Joint International Laboratory of Infection and Immunity, Huazhong University of Science and Technology, Wuhan 430022, China
- Correspondence: ; Tel.: +86-186-9615-9826
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11
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Zhang Y, Han J, Zhang X, Li F, Guo Y, He J, Mao R, Zhu H, Yu J, Huang Y, Yang F, Zhang J. Lower frequency of MDSCs was significantly related to functional cure in CHB patients treated with peginterferon. Liver Int 2023; 43:329-339. [PMID: 36453086 DOI: 10.1111/liv.15489] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 10/10/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND AND AIMS Myeloid-derived suppressor cells (MDSCs) and CD4+ regulatory T cells (Tregs) expand during chronic hepatitis B virus (HBV) infection and inhibit antiviral immunity. However, the relationship between antiviral effect and the frequencies of those immune suppressive cells after pegylated interferon α-2a (PegIFNα-2a) therapy is not clearly understood. This study aimed to investigate the contribution of monocytic MDSCs (mMDSCs) and CD4+ Tregs to functional cure (HBsAg seroclearance) after PegIFNα-2a therapy and evaluate the effect of PegIFNα-2a therapy on these cells. METHODS Flow cytometry analysis was performed along with longitudinal immune monitoring of 97 hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) patients receiving PegIFNα-2a weekly for 48 weeks. RESULTS The frequencies of mMDSCs and CD4+ Tregs increased in all HBV patients, and they were higher in the HBsAg persistence group than in the HBsAg seroclearance group. A significant decline in the frequency of mMDSCs was found in patients who realized functional cure after PegIFNα-2a treatment. In contrast, the frequency of CD4+ Tregs in both the HBsAg seroclearance and persistence groups significantly increased. Multivariate analyses indicated that the baseline serum HBsAg levels (p < .001) and mMDSCs frequency (p = .027) were independently associated with the HBsAg clearance, and the combined marker (HBsAg plus mMDSCs) displayed the highest specificity (93.1%) than any other markers in predicting HBsAg seroclearance. CONCLUSIONS These results suggest that a poor response to PegIFNα-2a treatment in CHB patients may be related to the frequencies of immune suppressive cells, while the therapeutic targeting of these cells might be effective in boosting anti-HBV immunity.
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Affiliation(s)
- Yao Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiajia Han
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Xueyun Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Fahong Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yifei Guo
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jingjing He
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Richeng Mao
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Haoxiang Zhu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jie Yu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Feifei Yang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Infectious Diseases and Biosecurity, Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, China.,Department of Infectious Diseases, Jing'An Branch of Huashan Hospital, Fudan University, Shanghai, China
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12
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Parlar YE, Ayar SN, Cagdas D, Balaban YH. Liver immunity, autoimmunity, and inborn errors of immunity. World J Hepatol 2023; 15:52-67. [PMID: 36744162 PMCID: PMC9896502 DOI: 10.4254/wjh.v15.i1.52] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 10/23/2022] [Accepted: 12/23/2022] [Indexed: 01/16/2023] Open
Abstract
The liver is the front line organ of the immune system. The liver contains the largest collection of phagocytic cells in the body that detect both pathogens that enter through the gut and endogenously produced antigens. This is possible by the highly developed differentiation capacity of the liver immune system between self-antigens or non-self-antigens, such as food antigens or pathogens. As an immune active organ, the liver functions as a gatekeeping barrier from the outside world, and it can create a rapid and strong immune response, under unfavorable conditions. However, the liver's assumed immune status is anti-inflammatory or immuno-tolerant. Dynamic interactions between the numerous populations of immune cells in the liver are key for maintaining the delicate balance between immune screening and immune tolerance. The anatomical structure of the liver can facilitate the preparation of lymphocytes, modulate the immune response against hepatotropic pathogens, and contribute to some of its unique immunological properties, particularly its capacity to induce antigen-specific tolerance. Since liver sinusoidal endothelial cell is fenestrated and lacks a basement membrane, circulating lymphocytes can closely contact with antigens, displayed by endothelial cells, Kupffer cells, and dendritic cells while passing through the sinusoids. Loss of immune tolerance, leading to an autoaggressive immune response in the liver, if not controlled, can lead to the induction of autoimmune or autoinflammatory diseases. This review mentions the unique features of liver immunity, and dysregulated immune responses in patients with autoimmune liver diseases who have a close association with inborn errors of immunity have also been the emphases.
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Affiliation(s)
- Yavuz Emre Parlar
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey.
| | - Sefika Nur Ayar
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
| | - Deniz Cagdas
- Department of Pediatric Immunology, Hacettepe University Ihsan Dogramaci Children's Hospital, Ankara 06100, Turkey
| | - Yasemin H Balaban
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
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13
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Borgna E, Prochetto E, Gamba JC, Marcipar I, Cabrera G. Role of myeloid-derived suppressor cells during Trypanosoma cruzi infection. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 375:117-163. [PMID: 36967151 DOI: 10.1016/bs.ircmb.2022.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
Abstract
Chagas disease (CD), caused by the protozoan parasite Trypanosoma cruzi, is the third largest parasitic disease burden globally. Currently, more than 6 million people are infected, mainly in Latin America, but international migration has turned CD into an emerging health problem in many nonendemic countries. Despite intense research, a vaccine is still not available. A complex parasite life cycle, together with numerous immune system manipulation strategies, may account for the lack of a prophylactic or therapeutic vaccine. There is substantial experimental evidence supporting that T. cruzi acute infection generates a strong immunosuppression state that involves numerous immune populations with regulatory/suppressive capacity. Myeloid-derived suppressor cells (MDSCs), Foxp3+ regulatory T cells (Tregs), regulatory dendritic cells and B regulatory cells are some of the regulatory populations that have been involved in the acute immune response elicited by the parasite. The fact that, during acute infection, MDSCs increase notably in several organs, such as spleen, liver and heart, together with the observation that depletion of those cells can decrease mouse survival to 0%, strongly suggests that MDSCs play a major role during acute T. cruzi infection. Accumulating evidence gained in different settings supports the capacity of MDSCs to interact with cells from both the effector and the regulatory arms of the immune system, shaping the outcome of the response in a very wide range of scenarios that include pathological and physiological processes. In this sense, the aim of the present review is to describe the main knowledge about MDSCs acquired so far, including several crosstalk with other immune populations, which could be useful to gain insight into their role during T. cruzi infection.
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14
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Amajala KC, Gudivada IP, Malla RR. Gamma Delta T Cells: Role in Immunotherapy of Hepatocellular Carcinoma. Crit Rev Oncog 2023; 28:41-50. [PMID: 38050980 DOI: 10.1615/critrevoncog.2023049893] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/07/2023]
Abstract
The most typical type of liver cancer or hepatocellular carcinoma (HCC) develops from hepatocyte loss. Non-alcoholic fatty liver disease (NAFLD), viral hepatitis C and cirrhosis are the leading causes of HCC. With the Hepatitis B vaccine and medicines, there are several treatments for HCC, including liver resection, ablation, transplantation, immunotherapy, gene therapy, radiation embolization, and targeted therapy. Currently, a wide range of studies are carried out on gene therapy to identify biomarkers and pathways, which help us identify the exact stage of the disorder and reduce its effects. γδT cells have recently received much interest as a potential cancer treatment method in adaptive immunotherapy. γδT cells can quickly form connections between receptor and ligand activation. They can clonally expand and are a significant source of cytokines and chemokines. The present review provides a comprehensive understanding on the function of γδT cells in immunotherapies and how they are used to treat HCC.
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Affiliation(s)
- Krishna Chaitanya Amajala
- Department of Biochemistry and Bioinformatics, GITAM School of Science, GITAM Deemed to be University, Visakhapatnam 530045, Andhra Pradesh, India
| | - Indu Priya Gudivada
- Department of Biochemistry and Bioinformatics, GITAM School of Science, GITAM Deemed to be University, Visakhapatnam 530045, Andhra Pradesh, India
| | - Rama Rao Malla
- Cancer Biology Laboratory, Department of Biochemistry and Bioinformatics, School of Science, Gandhi Institute of Technology and Management (GITAM) (Deemed to be University), Visakhapatnam-530045, Andhra Pradesh, India; Department of Biochemistry and Bioinformatics, School of Science, GITAM (Deemed to be University), Visakhapatnam-530045, Andhra Pradesh, India
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15
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Glover A, Zhang Z, Shannon-Lowe C. Deciphering the roles of myeloid derived suppressor cells in viral oncogenesis. Front Immunol 2023; 14:1161848. [PMID: 37033972 PMCID: PMC10076641 DOI: 10.3389/fimmu.2023.1161848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 03/10/2023] [Indexed: 04/11/2023] Open
Abstract
Myeloid derived suppressor cells (MDSCs) are a heterogenous population of myeloid cells derived from monocyte and granulocyte precursors. They are pathologically expanded in conditions of ongoing inflammation where they function to suppress both innate and adaptive immunity. They are subdivided into three distinct subsets: monocytic (M-) MDSC, polymorphonuclear (or neutrophilic) (PMN-) MDSC and early-stage (e-) MDSC that may exhibit differential function in different pathological scenarios. However, in cancer they are associated with inhibition of the anti-tumour immune response and are universally associated with a poor prognosis. Seven human viruses classified as Group I carcinogenic agents are jointly responsible for nearly one fifth of all human cancers. These viruses represent a large diversity of species, including DNA, RNA and retroviridae. They include the human gammaherpesviruses (Epstein Barr virus (EBV) and Kaposi's Sarcoma-Associated Herpesvirus (KSHV), members of the high-risk human papillomaviruses (HPVs), hepatitis B and C (HBV, HCV), Human T cell leukaemia virus (HTLV-1) and Merkel cell polyomavirus (MCPyV). Each of these viruses encode an array of different oncogenes that perturb numerous cellular pathways that ultimately, over time, lead to cancer. A prerequisite for oncogenesis is therefore establishment of chronic infection whereby the virus persists in the host cells without being eradicated by the antiviral immune response. Although some of the viruses can directly modulate the immune response to enable persistence, a growing body of evidence suggests the immune microenvironment is modulated by expansions of MDSCs, driven by viral persistence and oncogenesis. It is likely these MDSCs play a role in loss of immune recognition and function and it is therefore essential to understand their phenotype and function, particularly given the increasing importance of immunotherapy in the modern arsenal of anti-cancer therapies. This review will discuss the role of MDSCs in viral oncogenesis. In particular we will focus upon the mechanisms thought to drive the MDSC expansions, the subsets expanded and their impact upon the immune microenvironment. Importantly we will explore how MDSCs may modulate current immunotherapies and their impact upon the success of future immune-based therapies.
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16
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Ren H, Li W, Liu X, Zhao N. γδ T cells: The potential role in liver disease and implications for cancer immunotherapy. J Leukoc Biol 2022; 112:1663-1668. [PMID: 36098208 DOI: 10.1002/jlb.5mr0822-733rrr] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 08/31/2022] [Indexed: 01/04/2023] Open
Abstract
The γδ T cell subset was discovered over 30 years ago, yet continues to be an exciting and challenging component of the adaptive immune response. While γδ T cells represent a very small fraction of all T cells in humans, γδ T cells have a vital effect on human immunity, serving as a bridge between the innate and adaptive immune systems. The characteristics of γδ T cells include recognition of non-MHC restrictive antigens, as well as the ability to secrete an abundance of cytokines, suggesting that γδ T cells have high antitumor activity. As such, they have gained ample attention with respect to tumor immunotherapy in the last decade. The γδ T cell subset comprises up to ∼15-20% of the T-lymphocyte population in the liver, although the liver is recognized as an immune organ with primary immune functions, the role of γδ T cells in liver disease has not been established. Herein, we present a comprehensive overview of molecular mechanisms underlying immune γδ T cell activity in liver disease, including immune liver injury, viral hepatitis, cirrhosis, and hepatocellular carcinoma, and review γδ T cell-based clinical immunotherapeutic approaches.
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Affiliation(s)
- He Ren
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - WanJing Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Xin Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Na Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
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17
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Liang M, Liu Y, Zhang Z, Yang H, Dai N, Zhang N, Sun W, Guo Y, Kong J, Wang X, Wang M, Zhou F. Fusobacterium nucleatum induces MDSCs enrichment via activation the NLRP3 inflammosome in ESCC cells, leading to cisplatin resistance. Ann Med 2022; 54:989-1003. [PMID: 35435776 PMCID: PMC9891225 DOI: 10.1080/07853890.2022.2061045] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND To analyse the regulatory effect of Fusobacterium nucleatum (Fn) on NOD-like receptor protein 3 (NLRP3) and myeloid-derived suppressor cells (MDSCs) in oesophageal squamous cell carcinoma (ESCC) as well as its effect on cisplatin (CDDP) therapy and to explore its clinical significance. METHODS Fn infection, NLRP3 expression and MDSCs infiltration in ESCC tissues were detected by RNAscope and immunohistochemistry (IHC). The correlation between these three factors and the clinicopathological features and survival of ESCC patients was analysed. A coculture system of human peripheral blood monocytes (PBMCs) and ESCC cells was established to simulate the tumour microenvironment. In vitro and in vivo models were used to analyse the effects of Fn on the percentage of MDSCs in the coculture system and the NLRP3 expression level and CDDP sensitivity of ESCC cells. RESULTS Fn infection was consistent with high NLRP3 expression and MDSCs enrichment in ESCC tissues. Moreover, the survival time of ESCC patients was significantly shortened under Fn infection, high NLRP3 expression and MDSCs enrichment. In the in vitro and in vivo models, Fn induced abundant enrichment of MDSCs by inducing high expression of NLRP3 in ESCC cells and reducing the sensitivity of ESCC cells to CDDP. CONCLUSIONS Fn infection can induce high expression of NLRP3 in ESCC, lead to MDSCs enrichment, weaken the body's antitumour immunity, and lead to CDDP treatment resistance. The effective elimination of Fn and the inhibition of MDSCs enrichment may provide new strategies and treatments for ESCC.HighlightsThe survival of ESCC patients with Fn infection, high NLRP3 expression and MDSCs enrichment was significantly shortened.Fn infection could cause CDDP resistance in ESCC.Fn could induce the enrichment of MDSCs in the tumour microenvironment by activating NLRP3 in ESCC cells.
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Affiliation(s)
- Mengxia Liang
- Anyang Tumor Hospital, Anyang Tumor Hospital affiliated to Henan University of Science and Technology, Henan Key Medical Laboratory of Precise Prevention and Treatment of Esophageal Cancer, Anyang, China.,Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment; Henan Key Laboratory of Cancer Epigenetics; Cancer Hospital, The First Affiliated Hospital（College of Clinical Medicine）of Henan University of Science and Technology, Luoyang, China
| | - Yiwen Liu
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment; Henan Key Laboratory of Cancer Epigenetics; Cancer Hospital, The First Affiliated Hospital（College of Clinical Medicine）of Henan University of Science and Technology, Luoyang, China
| | - Zheyuan Zhang
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment; Henan Key Laboratory of Cancer Epigenetics; Cancer Hospital, The First Affiliated Hospital（College of Clinical Medicine）of Henan University of Science and Technology, Luoyang, China
| | - Haijun Yang
- Anyang Tumor Hospital, Anyang Tumor Hospital affiliated to Henan University of Science and Technology, Henan Key Medical Laboratory of Precise Prevention and Treatment of Esophageal Cancer, Anyang, China
| | - Ningtao Dai
- Anyang Tumor Hospital, Anyang Tumor Hospital affiliated to Henan University of Science and Technology, Henan Key Medical Laboratory of Precise Prevention and Treatment of Esophageal Cancer, Anyang, China
| | - Ning Zhang
- Anyang Tumor Hospital, Anyang Tumor Hospital affiliated to Henan University of Science and Technology, Henan Key Medical Laboratory of Precise Prevention and Treatment of Esophageal Cancer, Anyang, China
| | - Wei Sun
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment; Henan Key Laboratory of Cancer Epigenetics; Cancer Hospital, The First Affiliated Hospital（College of Clinical Medicine）of Henan University of Science and Technology, Luoyang, China
| | - Yibo Guo
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment; Henan Key Laboratory of Cancer Epigenetics; Cancer Hospital, The First Affiliated Hospital（College of Clinical Medicine）of Henan University of Science and Technology, Luoyang, China
| | - Jinyu Kong
- Henan Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment; Henan Key Laboratory of Cancer Epigenetics; Cancer Hospital, The First Affiliated Hospital（College of Clinical Medicine）of Henan University of Science and Technology, Luoyang, China
| | - Xiaopeng Wang
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Min Wang
- The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Fuyou Zhou
- Anyang Tumor Hospital, Anyang Tumor Hospital affiliated to Henan University of Science and Technology, Henan Key Medical Laboratory of Precise Prevention and Treatment of Esophageal Cancer, Anyang, China
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Ling S, You Z, Li Y, Zhang J, Zhao S, He Y, Chen X. The role of γδ T17 cells in cardiovascular disease. J Leukoc Biol 2022; 112:1649-1661. [PMID: 36073777 DOI: 10.1002/jlb.3mr0822-761rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/23/2022] [Accepted: 08/03/2022] [Indexed: 01/04/2023] Open
Abstract
Due to the ability of γδ T cells to bridge adaptive and innate immunity, γδ T cells can respond to a variety of molecular cues and acquire the ability to induce a variety of cytokines such as IL-17 family, IFN-γ, IL-4, and IL-10. IL-17+ γδ T cells (γδ T17 cells) populations have recently received considerable interest as they are the major early source of IL-17A in many immune response models. However, the exact mechanism of γδ T17 cells is still poorly understood, especially in the context of cardiovascular disease (CVD). CVD is the leading cause of death in the world, and it tends to be younger. Here, we offer a review of the cardiovascular inflammatory and immune functions of γδ T17 cells in order to understand their role in CVD, which may be the key to developing new clinical applications.
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Affiliation(s)
- Shaoxue Ling
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Zonghao You
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Yang Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Jian Zhang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Shuwu Zhao
- School of Intergrative Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Yongzhi He
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Xi Chen
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
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19
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Li YR, Wilson M, Yang L. Target tumor microenvironment by innate T cells. Front Immunol 2022; 13:999549. [PMID: 36275727 PMCID: PMC9582148 DOI: 10.3389/fimmu.2022.999549] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 09/23/2022] [Indexed: 12/08/2022] Open
Abstract
The immunosuppressive tumor microenvironment (TME) remains one of the most prevailing barriers obstructing the implementation of effective immunotherapy against solid-state cancers. Eminently composed of immunosuppressive tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) among others, the TME attenuates the effects of immune checkpoint blockade and adoptive cell therapies, mandating a novel therapy capable of TME remediation. In this review we explore the potential of three innate-like T cell subsets, invariant natural killer T (iNKT), mucosal-associated invariant T (MAIT) cells, and gamma delta T (γδT) cells, that display an intrinsic anti-TAM/MDSC capacity. Exhibiting both innate and adaptive properties, innate-like T cell types express a subset-specific TCR with distinct recombination, morphology, and target cell recognition, further supplemented by a variety of NK activating receptors. Both NK activating receptor and TCR activation result in effector cell cytotoxicity against targeted immunosuppressive cells for TME remediation. In addition, innate-like T cells showcase moderate levels of tumor cell killing, providing dual antitumor and anti-TAM/MDSC function. This latent antitumor capacity can be further bolstered by chimeric antigen receptor (CAR) engineering for recognition of tumor specific antigens to enhance antitumor targeting. In contrast with established CAR-T cell therapies, adoption of these innate-like cell types provides an enhanced safety profile without the risk of graft versus host disease (GvHD), due to their non-recognition of mismatched major histocompatibility complex (MHC) molecules, for use as widely accessible, allogeneic “off-the-shelf” cancer immunotherapy.
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Affiliation(s)
- Yan-Ruide Li
- Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, Los Angeles, CA, United States
| | - Matthew Wilson
- Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, Los Angeles, CA, United States
| | - Lili Yang
- Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, Los Angeles, CA, United States
- Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, United States
- Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, United States
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
- *Correspondence: Lili Yang,
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20
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Chen S, Gao Y, Wang Y, Daemen T. The combined signatures of hypoxia and cellular landscape provides a prognostic and therapeutic biomarker in hepatitis B virus-related hepatocellular carcinoma. Int J Cancer 2022; 151:809-824. [PMID: 35467769 PMCID: PMC9543189 DOI: 10.1002/ijc.34045] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 03/13/2022] [Accepted: 04/05/2022] [Indexed: 11/18/2022]
Abstract
Prognosis and treatment options of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) are generally based on tumor burden and liver function. Yet, tumor growth and therapeutic resistance of HBV-HCC are strongly influenced by intratumoral hypoxia and cells infiltrating the tumor microenvironment (TME). We, therefore, studied whether linking parameters associated with hypoxia and TME cells could have a better prediction of prognosis and therapeutic responses. Quantification of 109 hypoxia-related genes and 64 TME cells was performed in 452 HBV-HCC tumors. Prognostic hypoxia and TME cells signatures were determined based on Cox regression and meta-analysis for generating the Hypoxia-TME classifier. Thereafter, the prognosis, tumor, and immune characteristics as well as the benefit of therapies in Hypoxia-TME defined subgroups were analyzed. Patients in the Hypoxialow /TMEhigh subgroup showed a better prognosis and therapeutic responses than any other subgroups, which can be well elucidated based on the differences in terms of immune-related molecules, tumor somatic mutations, and cancer cellular signaling pathways. Notably, our analysis furthermore demonstrated the synergistic influence of hypoxia and TME on tumor metabolism and proliferation. Besides, the classifier allowed a further subdivision of patients with early- and late-HCC stages. In addition, the Hypoxia-TME classifier was validated in another independent HBV-HCC cohort (n = 144) and several pan-cancer cohorts. Overall, the Hypoxia-TME classifier showed a pretreatment predictive value for prognosis and therapeutic responses, which might provide new directions for strategizing patients with optimal therapies.
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Affiliation(s)
- Shipeng Chen
- Department of Medical Microbiology and Infection Prevention, Tumor Virology and Cancer ImmunotherapyUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
| | - Yuzhen Gao
- Department of Clinical LaboratorySir Run Run Shaw Hospital, Zhejiang University School of MedicineHangzhouZhejiangChina
| | - Ying Wang
- Department of Laboratory MedicineShanghai Eastern Hepatobiliary Surgery HospitalShanghaiChina
- Research Center for Translational MedicineShanghai East Hospital, School of Life Sciences and Technology, Tongji UniversityShanghaiChina
| | - Toos Daemen
- Department of Medical Microbiology and Infection Prevention, Tumor Virology and Cancer ImmunotherapyUniversity Medical Center Groningen, University of GroningenGroningenThe Netherlands
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21
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Madecassic acid alleviates colitis-associated colorectal cancer by blocking the recruitment of myeloid-derived suppressor cells via the inhibition of IL-17 expression in γδT17 cells. Biochem Pharmacol 2022; 202:115138. [PMID: 35700756 DOI: 10.1016/j.bcp.2022.115138] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 06/03/2022] [Accepted: 06/07/2022] [Indexed: 11/20/2022]
Abstract
INTRODUCTION Madecassic acid (MA), a triterpene compound isolated from Centella Asiatica herbs, has previously been shown to attenuate colitis induced by DSS in mice. In the present study, we address whether and how MA ameliorates colitis-associated colorectal cancer (CAC), which accounts for a considerable proportion of colorectal cancer. METHODS CAC was induced by AOM/DSS in mice, and MA was administered orally once a day. To identify the source cells of IL-17 and the target cells for MA reducing the expression of IL-17 in the colons of CAC mice, single-cell suspensions were prepared from the colons of CAC mice and analyzed by flow cytometry. An adoptive transfer experiment was performed to verify the importance of the decreasing γδT17 cell population in the anti-CAC effect of MA. RESULTS Oral administration of MA reduced the burden and incidence of tumors in the CAC mice. MA decreased the number of MDSCs in the colon tissues of CAC mice and ameliorated anti-tumor immune responses. MA could prevent the migration of MDSCs by inhibiting the activation of γδT17 cells and the expression of chemokines. The population of activated-γδT17 cells in the tumor microenvironment of CAC mice positively correlated with the number of MDSCs and tumors as well as tumor load. Moreover, the anti-CAC effect of MA was significantly counteracted by the adoptive transfer of γδT17 cells. CONCLUSIONS MA alleviates CAC by blocking the recruitment of MDSCs to increase the population of anti-tumor immune cells in tumor microenvironment via inhibition of the activation of γδT17 cells.
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22
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Targeting Immunosuppressive Tumor-Associated Macrophages Using Innate T Cells for Enhanced Antitumor Reactivity. Cancers (Basel) 2022; 14:cancers14112749. [PMID: 35681730 PMCID: PMC9179365 DOI: 10.3390/cancers14112749] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/17/2022] [Accepted: 05/30/2022] [Indexed: 01/03/2023] Open
Abstract
The field of T cell-based and chimeric antigen receptor (CAR)-engineered T (CAR-T) cell-based antitumor immunotherapy has seen substantial developments in the past decade; however, considerable issues, such as graft-versus-host disease (GvHD) and tumor-associated immunosuppression, have proven to be substantial roadblocks to widespread adoption and implementation. Recent developments in innate immune cell-based CAR therapy have opened several doors for the expansion of this therapy, especially as it relates to allogeneic cell sources and solid tumor infiltration. This study establishes in vitro killing assays to examine the TAM-targeting efficacy of MAIT, iNKT, and γδT cells. This study also assesses the antitumor ability of CAR-engineered innate T cells, evaluating their potential adoption for clinical therapies. The in vitro trials presented in this study demonstrate the considerable TAM-killing abilities of all three innate T cell types, and confirm the enhanced antitumor abilities of CAR-engineered innate T cells. The tumor- and TAM-targeting capacity of these innate T cells suggest their potential for antitumor therapy that supplements cytotoxicity with remediation of tumor microenvironment (TME)-immunosuppression.
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23
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Liu B, He X, Wang Y, Huang JW, Zheng YB, Li Y, Lu LG. Bibliometric Analysis of γδ T Cells as Immune Regulators in Cancer Prognosis. Front Immunol 2022; 13:874640. [PMID: 35493488 PMCID: PMC9048597 DOI: 10.3389/fimmu.2022.874640] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 03/15/2022] [Indexed: 11/13/2022] Open
Abstract
γδ T cells are one of only three immune cell types that express antigen receptors that undergo somatic recombination, and they contribute to immune responses to infection, cellular transformation, and tissue damage. As a “bridge” between the innate and adaptive immune systems, γδ T cells have been noted to be involved in various immune responses during cancer progression. The purpose of our study was to review current published information on γδ T cells and investigate their functions in different types of malignancy using bibliometric and bioinformatic methods. Our results indicated that studies on γδ T cells and cancer progression increased from 2014, and the number had peaked by 2021. We discovered that there is international cooperation in the performance of studies among 26 countries, where China was identified as the most productive with the highest citations. Using keyword co-occurrence analysis, we found that among all the cancer types investigated, gastric and breast cancers were most closely related to γδ T cells. Furthermore, interleukin (IL)-17 and IL-2 were the most common cytokines linked to γδ T cells and our investigation of their potential involvement in the prognosis of gastric and breast cancers, identified their different roles in various malignancies. Thus, we concluded that γδ T cells might influence the progression of different cancers in diverse ways.
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Affiliation(s)
| | | | | | | | | | - Yong Li
- *Correspondence: Yong Li, ; Li-gong Lu,
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24
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Wang X, Xie Q. Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD) and Viral Hepatitis. J Clin Transl Hepatol 2022; 10:128-133. [PMID: 35233381 PMCID: PMC8845159 DOI: 10.14218/jcth.2021.00200] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 08/19/2021] [Accepted: 09/07/2021] [Indexed: 12/04/2022] Open
Abstract
A new definition of metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed in 2020. The change from nonalcoholic fatty liver disease (NAFLD) to MAFLD highlights the metabolic abnormalities that accompany fatty liver. The diagnosis of MAFLD does not require exclusion of secondary causes of liver diseases and alcohol consumption. Thus, MAFLD may coexist with other types of liver diseases, such as viral hepatitis, a disease that remains the most common cause of liver disease-related death. With the increasing prevalence of MAFLD, patients with coincidental MAFLD and viral hepatitis are frequently encountered in clinical practice. In this review, we mainly summarize the mutual relationship between hepatitis B/C and systematic metabolism dysfunction related to MAFLD. We discuss the impact of MAFLD on progression of viral hepatitis and the therapies. Some unaddressed clinical problems related to concomitant MAFLD and viral hepatitis are also identified.
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Affiliation(s)
- Xiaolin Wang
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qing Xie
- Department of Infectious Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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25
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Zhang J, Liu K, Zhang G, Ling N, Chen M. Interleukin-17A pretreatment attenuates the anti-hepatitis B virus efficacy of interferon-alpha by reducing activation of the interferon-stimulated gene factor 3 transcriptional complex in hepatitis B virus-expressing HepG2 cells. Virol J 2022; 19:28. [PMID: 35144643 PMCID: PMC8830041 DOI: 10.1186/s12985-022-01753-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/26/2022] [Indexed: 11/16/2022] Open
Abstract
Background Some cytokine signaling pathways can interact with interferon (IFN)-α pathway and thus regulate cell responses to IFN-α. Levels of the pro-inflammatory cytokine interleukin-17A (IL-17A) were found to be elevated in both the peripheral blood and liver in chronic hepatitis B (CHB) patients. However, how IL-17A affects the anti-HBV activity of IFN-α remains unclear. Methods The effects of IL-17A on anti-HBV activity of IFN-α were evaluated in HBV-expressing HepG2 cells (HepG2-HBV1.3) with IL-17A pretreatment and IFN-α stimulation. Culture supernatant levels of HBsAg, HBeAg, and HBV DNA, or intracellular expression of HBsAg and HBcAg were detected by ELISA, real-time quantitative PCR (RT-qPCR), or western blotting (WB). The expression of canonical IFN-α signaling pathway components, including the interferon-α/β receptor (IFNAR), Janus Kinase 1 (JAK1), Tyrosine Kinase 2 (TYK2), the Interferon Stimulated Gene Factor 3 complex (ISGF3) and IFN-stimulated genes (ISGs), was also examined by RT-qPCR, Immunofluorescence or WB. The effects of IL-17A were further investigated by the suppression of the IL-17A pathway with a TRAF6 inhibitor. Results Compared to IFN-α stimulation alone, IL-17A pretreatment followed by IFN-α stimulation increased the levels of HBsAg, HBeAg, and HBV DNA, and decreased the levels of ISGF3 complex (phosphorylated (p)-signal transducer and activator of transcription (STAT1)/p-STAT2/IRF9) and antiviral-related ISGs (ISG15, ISG20 and Mx1). Interestingly, IL-17A pretreatment increased the expression of suppressor of cytokine signaling (SOCS) 1, SOCS3 and USP18, which were also the ISGs negatively regulating activity of ISGF3. Moreover, IFNAR1 protein expression declined more sharply in the group with IL-17A pretreatment than in the group with IFN-α stimulation alone. Blocking the IL-17A pathway reversed the effects of IL-17A on the IFN-α-induced activation of ISGF3 and anti-HBV efficacy. Conclusions Our results demonstrate that IL-17A pretreatment could attenuate IFN-α-induced anti-HBV activity by upregulating negative regulators of the critical transcriptional ISGF3 complex. Thus, this might be a potential target for improving response to IFN-α therapy. Supplementary Information The online version contains supplementary material available at 10.1186/s12985-022-01753-x.
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Affiliation(s)
- Jiaxuan Zhang
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Kai Liu
- Department of Clinical Laboratory, The People's Hospital of Leshan, Chongqing, China
| | - Gaoli Zhang
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ning Ling
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Min Chen
- Department of Infectious Diseases, Institute for Viral Hepatitis, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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Cho HJ, Cheong JY. Role of Immune Cells in Patients with Hepatitis B Virus-Related Hepatocellular Carcinoma. Int J Mol Sci 2021; 22:ijms22158011. [PMID: 34360777 PMCID: PMC8348470 DOI: 10.3390/ijms22158011] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 12/17/2022] Open
Abstract
Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and adaptive immune responses that engage various immune cells. Natural killer (NK) cells are associated with early antiviral and antitumor properties. On the other hand, inflammatory cells release various cytokines and chemokines that may promote HCC tumorigenesis. Moreover, immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressive cells play a critical role in hepatocarcinogenesis. HBV-specific CD8+ T cells have been identified as pivotal players in antiviral responses, whilst extremely activated CD8+ T cells induce enormous inflammatory responses, and chronic inflammation can facilitate hepatocarcinogenesis. Controlling and maintaining the balance in the immune system is an important aspect in the management of HBV-related HCC. We conducted a review of the current knowledge on the immunopathogenesis of HBV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC based on the recent studies on innate and adaptive immune cell dysfunction in HBV-related HCC.
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Affiliation(s)
| | - Jae-Youn Cheong
- Correspondence: ; Tel.: +82-31-219-6939; Fax: +82-31-219-5999
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27
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CD8 + T cells inhibit metastasis and CXCL4 regulates its function. Br J Cancer 2021; 125:176-189. [PMID: 33795809 PMCID: PMC8292398 DOI: 10.1038/s41416-021-01338-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 01/21/2021] [Accepted: 02/23/2021] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND The mechanism by which immune cells regulate metastasis is unclear. Understanding the role of immune cells in metastasis will guide the development of treatments improving patient survival. METHODS We used syngeneic orthotopic mouse tumour models (wild-type, NOD/scid and Nude), employed knockout (CD8 and CD4) models and administered CXCL4. Tumours and lungs were analysed for cancer cells by bioluminescence, and circulating tumour cells were isolated from blood. Immunohistochemistry on the mouse tumours was performed to confirm cell type, and on a tissue microarray with 180 TNBCs for human relevance. TCGA data from over 10,000 patients were analysed as well. RESULTS We reveal that intratumoral immune infiltration differs between metastatic and non-metastatic tumours. The non-metastatic tumours harbour high levels of CD8+ T cells and low levels of platelets, which is reverse in metastatic tumours. During tumour progression, platelets and CXCL4 induce differentiation of monocytes into myeloid-derived suppressor cells (MDSCs), which inhibit CD8+ T-cell function. TCGA pan-cancer data confirmed that CD8lowPlatelethigh patients have a significantly lower survival probability compared to CD8highPlateletlow. CONCLUSIONS CD8+ T cells inhibit metastasis. When the balance between CD8+ T cells and platelets is disrupted, platelets produce CXCL4, which induces MDSCs thereby inhibiting the CD8+ T-cell function.
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Agerholm R, Bekiaris V. Evolved to protect, designed to destroy: IL-17-producing γδ T cells in infection, inflammation, and cancer. Eur J Immunol 2021; 51:2164-2177. [PMID: 34224140 DOI: 10.1002/eji.202049119] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 07/02/2021] [Indexed: 11/09/2022]
Abstract
T cells of the gamma delta (γδ) lineage are evolutionary conserved from jawless to cartilaginous and bony fish to mammals and represent the "swiss army knife" of the immune system capable of antigen-dependent or independent responses, memory, antigen presentation, regulation of other lymphocytes, tissue homeostasis, and mucosal barrier maintenance, to list a few. Over the last 10 years, γδ T cells that produce the cytokine IL-17 (γδT17) have taken a leading position in our understanding of how our immune system battles infection, inflicts tissue damage during inflammation, and gets rewired by the tumor microenvironment. A lot of what we know about γδT17 cells stems from mouse models, however, increasing evidence implicates these cells in numerous human diseases. Herein, we aim to give an overview of the most common mouse models that have been used to study the role of γδT17 cells in infection, inflammation, and cancer, while at the same time we will evaluate evidence for their importance in humans. We hope and believe that in the next 10 years, means to take advantage of the protective and destructive properties of γδ T and in particular γδT17 cells will be part of our standard immunotherapy toolkit.
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Affiliation(s)
- Rasmus Agerholm
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Vasileios Bekiaris
- Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark
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29
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Sehgal R, Kaur N, Ramakrishna G, Trehanpati N. Immune Surveillance by Myeloid-Derived Suppressor Cells in Liver Diseases. Dig Dis 2021; 40:301-312. [PMID: 34157708 DOI: 10.1159/000517459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 05/27/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) are immunosuppressive in nature, originate in the bone marrow, and are mainly found in the blood, spleen, and liver. In fact, liver acts as an important organ for induction and accumulation of MDSCs, especially during infection, inflammation, and cancer. In humans and rodents, models of liver diseases revealed that MDSCs promote regeneration and drive the inflammatory processes, leading to hepatitis, fibrogenesis, and cirrhosis, ultimately resulting in hepatocellular carcinoma. SUMMARY This brief review is focused on the in-depth understanding of the key molecules involved in the expansion and regulation of MDSCs and their underlying immunosuppressive mechanisms in liver diseases. KEY MESSAGE Modulated MDSCs can be used for therapeutic purposes in inflammation, cancer, and sepsis.
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Affiliation(s)
- Rashi Sehgal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.,Amity Institute of Biotechnology (AIB), Amity University, Noida, India
| | - Navkiran Kaur
- Amity Institute of Biotechnology (AIB), Amity University, Noida, India
| | - Gayatri Ramakrishna
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Nirupma Trehanpati
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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30
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Gogoi D, Borkakoty B, Biswas D, Yadav K, Patel V. Characteristics of Circulatory γδ T cells in Patients with Symptomatic Chronic Hepatitis B Infection. Viral Immunol 2021; 34:483-490. [PMID: 34096794 DOI: 10.1089/vim.2020.0314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B is a viral infection that can cause serious liver disease. Chronic hepatitis B (CHB) infection places individuals at higher risk of developing cirrhosis of the liver and hepatocellular cancer. Immune dysfunction, including altered distribution and functional status of T cell immunity, is a contributor to hepatitis B virus (HBV) pathogenesis. In this study, we examined the distribution of circulating γδ T cell subpopulations and levels of cell surface expression of suppressive markers on γδ T cells in individuals with CHB infection and clinical liver disease. A significantly higher proportion of terminally differentiated (TEMRA) (CD27-CD45RA+) γδ T cells along with significantly lower percentages of central memory (CD27+CD45RA-) and effector memory (CD27-CD45RA-) γδ T cells were observed in peripheral blood of these individuals. The expression of exhaustion markers-Tim-3 and Lag-3 was elevated in γδ T cells from CHB-infected individuals compared with healthy controls (HC) and blockade of these exhaustion markers resulted in restoration of interferon gamma (IFN-γ) secretion by γδ T cells. In addition, γδ T cells from CHB patients expressed increased levels of CD69, another important regulator of immune responses. Together, these results suggest that CHB patients with clinical sign of liver disease have TEMRA γδ T cells with a potentially exhausted phenotype that may in turn impair their immunoregulatory role and facilitate pathogenesis of CHB disease.
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Affiliation(s)
- Dimpu Gogoi
- Department of Biochemistry and Virology, National Institute for Research in Reproductive Health, Indian Council of Medical Research, Mumbai, India.,Virology Section, Regional Medical Research Centre, Northeast Region, Indian Council of Medical Research, Dibrugarh, India
| | - Biswajyoti Borkakoty
- Virology Section, Regional Medical Research Centre, Northeast Region, Indian Council of Medical Research, Dibrugarh, India
| | - Dipankar Biswas
- Virology Section, Regional Medical Research Centre, Northeast Region, Indian Council of Medical Research, Dibrugarh, India
| | - Kaushal Yadav
- Virology Section, Regional Medical Research Centre, Northeast Region, Indian Council of Medical Research, Dibrugarh, India
| | - Vainav Patel
- Department of Biochemistry and Virology, National Institute for Research in Reproductive Health, Indian Council of Medical Research, Mumbai, India
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Kim BS, Kuen DS, Koh CH, Kim HD, Chang SH, Kim S, Jeon YK, Park YJ, Choi G, Kim J, Kang KW, Kim HY, Kang SJ, Hwang S, Shin EC, Kang CY, Dong C, Chung Y. Type 17 immunity promotes the exhaustion of CD8 + T cells in cancer. J Immunother Cancer 2021; 9:jitc-2021-002603. [PMID: 34083422 PMCID: PMC8183213 DOI: 10.1136/jitc-2021-002603] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/29/2021] [Indexed: 12/20/2022] Open
Abstract
Background Multiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8+ tumor-infiltrating lymphocytes (TILs) remain unclear. Methods To determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8+ TILs in Il17a−/− mice, Il17aCreR26DTA mice, RORγt inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice. Anti-CD4 or anti-Ly6G antibodies were used to deplete CD4+ T cells or CD11b+Gr-1hi myeloid cells in vivo, respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset. Results Depletion of CD4+ T cells promotes the exhaustion of CD8+ T cells with a concomitant increase in IL-17-producing CD8+ T (Tc17) cells in the tumor. Unlike IFN-γ-producing CD8+ T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103+KLRG1−IL-7Rαhi tissue resident memory-like phenotypes and are poorly cytolytic. Adoptive transfer of IL-17-producing tumor-specific T cells increases, while depletion of IL-17-producing cells decreases, the frequency of PD-1hiTim3+TOX+ terminally exhausted CD8+ T cells in the tumor. Blockade of IL-17 or RORγt pathway inhibits exhaustion of CD8+ T cells and also delays tumor growth in vivo. Consistent with these results, human TCGA analyses reveal a strong positive correlation between type 17 and CD8+ T cell exhaustion signature gene sets in multiple cancers. Conclusion IL-17-producing cells promote terminal exhaustion of CD8+ T cells and tumor progression in vivo, which can be reversed by blockade of IL-17 or RORγt pathway. These findings unveil a novel role for IL-17-producing cells as tumor-promoting cells facilitating CD8+ T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy.
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Affiliation(s)
- Byung-Seok Kim
- Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea .,Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, South Korea
| | - Da-Sol Kuen
- Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.,BK21 program, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Choong-Hyun Koh
- Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Hyung-Don Kim
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.,Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Seon Hee Chang
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sehui Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.,Cancer Research Institute, Seoul National University, Seoul, South Korea
| | - Yoon Kyung Jeon
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.,Cancer Research Institute, Seoul National University, Seoul, South Korea
| | - Young-Jun Park
- Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.,Department of Pharmacy, Jeju National University, Jeju, South Korea
| | - Garam Choi
- Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Jiyeon Kim
- Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea.,BK21 program, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Keon Wook Kang
- BK21 program, College of Pharmacy, Seoul National University, Seoul, South Korea.,Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Hye Young Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea
| | - Suk-Jo Kang
- Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
| | - Shin Hwang
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Eui-Cheol Shin
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
| | - Chang-Yuil Kang
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Chen Dong
- Institute for Immunology and School of Medicine, Tsinghua University, Beijing, China
| | - Yeonseok Chung
- Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea .,BK21 program, College of Pharmacy, Seoul National University, Seoul, South Korea
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Chen W, Lai D, Li Y, Wang X, Pan Y, Fang X, Fan J, Shu Q. Neuronal-Activated ILC2s Promote IL-17A Production in Lung γδ T Cells During Sepsis. Front Immunol 2021; 12:670676. [PMID: 33995408 PMCID: PMC8119647 DOI: 10.3389/fimmu.2021.670676] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/15/2021] [Indexed: 01/13/2023] Open
Abstract
Background Studies have revealed important roles for IL-17A in the development of acute lung injury (ALI) following sepsis. However, the mechanism underlying the regulation of lung IL-17A remains to be fully addressed. Recent studies suggested the effect of neuromedin U (NMU) on immune cell activation and the role of group 2 innate lymphoid cells (ILC2s) in the modulation of IL-17A production. We aimed to gain in-depth insight into the mechanism underlying sepsis-induced lung IL-17A production, particularly, the role of NMU in mediating neuronal regulation of ILC2s and IL-17A-producing γδ T cells activation in sepsis. Methods Wild type mice were subjected to cecal ligation and puncture (CLP) to induce sepsis with or without intraperitoneal injection of NMU. The levels of ILC2s, γδ T cells, IL-17A, NMU and NMU receptor 1 (NMUR1) in the lung were then measured. In order to determine the role of NMU signaling in ILC2 activation and the role of ILC2-released IL-9 in ILC2-γδ T cell interaction, ILC2s were sorted, and the genes of nmur1 and il9 in the ILC2s were knocked down using CRISPR/Cas9. The genetically manipulated ILC2s were then co-cultured with lung γδ T cells, and the levels of IL-17A from co-culture systems were measured. Results In septic mice, the levels of NMU, IL-17A, ILC2s, and IL-17A-producing γδ T cells in the lung are significantly increased, and the expression of NMUR1 in ILC2s is increased as well. Exogenous NMU further augments these increases. The main source of IL-17A in response to CLP is γδ T cells, and lung nmur1 is specifically expressed in ILC2s. In vitro co-culture of ILC2s and γδ T cells leads to increased number of γδ T cells and higher production of IL-17A from γδ T cells, and these alterations are further augmented by septic treatment and exogenous NMU. Genetic knockdown of nmur1 or il9 in ILC2s attenuated the upregulation of γδ T cells and IL-17A production. Conclusion In sepsis, NMU acting through NMUR1 in lung ILC2s initiates the ILC2 activation, which, in turn, promote IL-17A-producing γδ T cell expansion and secretion of IL-17A. ILC2-derived IL-9 plays an important role in mediating γδ T cell expansion and IL-17A production. This study explores a new mechanism underlying neuronal regulation of innate immunity in sepsis.
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Affiliation(s)
- Weiwei Chen
- Department of Thoracic and Cardiovascular Surgery, National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Dengming Lai
- Department of Thoracic and Cardiovascular Surgery, National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuehua Li
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, United States
| | - Xueke Wang
- Department of Thoracic and Cardiovascular Surgery, National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yihang Pan
- Department of Thoracic and Cardiovascular Surgery, National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiangming Fang
- Department of Anesthesiology and Intensive Care Unit, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jie Fan
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States.,Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, United States.,McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, United States
| | - Qiang Shu
- Department of Thoracic and Cardiovascular Surgery, National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Hou W, Wu X. Diverse Functions of γδ T Cells in the Progression of Hepatitis B Virus and Hepatitis C Virus Infection. Front Immunol 2021; 11:619872. [PMID: 33597951 PMCID: PMC7882476 DOI: 10.3389/fimmu.2020.619872] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/17/2020] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are primary risk factors for a wide spectrum of liver diseases that severely affect human health. The liver is an immunological organ that has an abundance of immune cells. Thus, various innate or adaptive immune cells are involved in the progression of HBV or HCV infection. Among those cells, a unique kind of immune cell, the γδ T cell, contributes to promoting or inhibiting the progression of liver diseases. To reveal the diverse roles of γδ T cells in HBV or HCV infection, the properties and functions of these cells in human and mouse models are analyzed. Here, we briefly describe the characteristics and functions of γδ T cells subsets in liver diseases. Then, we fully discuss the diverse roles of γδ T cells in the progression of HBV or HCV infection, including stages of acute infection, chronic infection, liver cirrhosis, and hepatocellular carcinoma. Finally, the functions and existing problems of γδ T cells in HBV or HCV infection are summarized. A better understanding of the function of γδ T cells during the progression of HBV and HCV infection will be helpful for the treatment of virus infection.
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Affiliation(s)
- Wen Hou
- Key Laboratory for Critical Care Medicine of the Ministry of Health, Tianjin First Central Hospital, Tianjin, China.,State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China
| | - Xiaoli Wu
- School of Life Sciences, Tianjin University, Tianjin, China
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Ruf B, Heinrich B, Greten TF. Immunobiology and immunotherapy of HCC: spotlight on innate and innate-like immune cells. Cell Mol Immunol 2021; 18:112-127. [PMID: 33235387 PMCID: PMC7852696 DOI: 10.1038/s41423-020-00572-w] [Citation(s) in RCA: 206] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 09/29/2020] [Indexed: 12/24/2022] Open
Abstract
Immune-based therapies such as immune checkpoint inhibitors have revolutionized the systemic treatment of various cancer types. The therapeutic application of monoclonal antibodies targeting inhibitory pathways such as programmed cell death-1(PD-1)/programmed cell death ligand 1 (PD-L1) and CTLA-4 to cells of the adaptive immune system has recently been shown to generate meaningful improvement in the clinical outcome of hepatocellular carcinoma (HCC). Nevertheless, current immunotherapeutic approaches induce durable responses in only a subset of HCC patients. Since immunologic mechanisms such as chronic inflammation due to chronic viral hepatitis or alcoholic and nonalcoholic fatty liver disease play a crucial role in the initiation, development, and progression of HCC, it is important to understand the underlying mechanisms shaping the unique tumor microenvironment of liver cancer. The liver is an immunologic organ with large populations of innate and innate-like immune cells and is exposed to bacterial, viral, and fungal antigens through the gut-liver axis. Here, we summarize and highlight the role of these cells in liver cancer and propose strategies to therapeutically target them. We also discuss current immunotherapeutic strategies in HCC and outline recent advances in our understanding of how the therapeutic potential of these agents might be enhanced.
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Affiliation(s)
- Benjamin Ruf
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Bernd Heinrich
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tim F Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Centre for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
- NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, 20892, USA.
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35
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Innate lymphocytes: pathogenesis and therapeutic targets of liver diseases and cancer. Cell Mol Immunol 2020; 18:57-72. [PMID: 33041339 DOI: 10.1038/s41423-020-00561-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023] Open
Abstract
The liver is a lymphoid organ with unique immunological properties, particularly, its predominant innate immune system. The balance between immune tolerance and immune activity is critical to liver physiological functions and is responsible for the sensitivity of this organ to numerous diseases, including hepatotropic virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, autoimmune liver disease, and liver cancer, which are major health problems globally. In the past decade, with the discovery of liver-resident natural killer cells, the importance of innate lymphocytes with tissue residency has gradually become the focus of research. In this review, we address the current knowledge regarding hepatic innate lymphocytes with unique characteristics, including NK cells, ILC1/2/3s, NKT cells, γδ T cells, and MAIT cells, and their potential roles in liver homeostasis maintenance and the progression of liver diseases and cancer. A better understanding of the immunopathogenesis of hepatic innate lymphocytes will be helpful for proposing effective treatments for liver diseases and cancer.
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36
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Bonilla CM, McGrath NA, Fu J, Xie C. Immunotherapy of hepatocellular carcinoma with infection of hepatitis B or C virus. HEPATOMA RESEARCH 2020; 6:68. [PMID: 33134550 PMCID: PMC7597818 DOI: 10.20517/2394-5079.2020.58] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) has one of highest mortalities globally amongst cancers, but has limited therapeutic options once in the advanced stage. Hepatitis B or C virus infection are the most common drivers for HCC carcinogenesis, triggering chronic liver inflammation and adding to the complexity of the immune microecosystem of HCC. The emergence of immunotherapy has afforded a new avenue of therapeutic options for patients with advanced HCC with a history of hepatitis B or C virus infection. This article reviews the change of immunity elicited by hepatitis B or C virus infection, the immune feature of HCC, and the clinical evidence for immunotherapy in advanced HCC and discusses future directions in this field.
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Affiliation(s)
- Cecilia Monge Bonilla
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Nicole A McGrath
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jianyang Fu
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Changqing Xie
- Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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37
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Hepatitis B surface antigen seroclearance: Immune mechanisms, clinical impact, importance for drug development. J Hepatol 2020; 73:409-422. [PMID: 32333923 DOI: 10.1016/j.jhep.2020.04.013] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 04/03/2020] [Accepted: 04/07/2020] [Indexed: 12/16/2022]
Abstract
HBsAg seroclearance occurs rarely in the natural history of chronic hepatitis B (CHB) infection and is associated with improved clinical outcomes. Many factors are associated with HBsAg seroconversion, including immune and viral factors. However, the immune mechanisms associated with HBsAg seroclearance are still difficult to elucidate. HBsAg seroclearance is the ideal aim of HBV treatment. Unfortunately, this goal is rarely achieved with current treatments. Understanding the mechanisms of HBsAg loss appears to be important for the development of curative HBV treatments. While studies from animal models give insights into the potential immune mechanisms and interactions occurring between the immune system and HBsAg, they do not recapitulate all features of CHB in humans and are subject to variability due to their complexity. In this article, we review recent studies on these immune factors, focusing on their influence on CHB progression and HBsAg seroconversion. These data provide new insights for the development of therapeutic approaches to partially restore the anti-HBV immune response. Targeting HBsAg will ideally relieve the immunosuppressive effects on the immune system and help to restore anti-HBV immune responses.
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Gardinali NR, Marchevsky RS, Oliveira JM, Pelajo-Machado M, Kugelmeier T, Castro MP, Silva ACA, Pinto DP, Fonseca LB, Vilhena LS, Pereira HM, Lima SMB, Miranda EH, Trindade GF, Linhares JHR, Silva SA, Melgaço JG, Alves AMB, Moran J, Silva MCC, Soares-Bezerra RJ, Soriano A, Bentes GA, Bottino FO, Salvador Castro Faria SB, Nudelman RF, Lopes CAA, Perea JAS, Sarges K, Andrade MCR, Motta MCVA, Freire MS, Souza TML, Schmidt-Chanasit J, Pinto MA. Sofosbuvir shows a protective effect against vertical transmission of Zika virus and the associated congenital syndrome in rhesus monkeys. Antiviral Res 2020; 182:104859. [PMID: 32649965 DOI: 10.1016/j.antiviral.2020.104859] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 06/08/2020] [Accepted: 06/12/2020] [Indexed: 12/15/2022]
Abstract
The outbreaks of Zika virus (ZIKV) infection in Brazil, 2015-2016, were associated with severe congenital malformations. Our translational study aimed to test the efficacy of the antiviral agent sofosbuvir (SOF) against vertical transmission of ZIKV and the associated congenital syndrome (CZS), using a rhesus monkey model. Eight pregnant macaques were successfully infected during the organogenesis phase with a Brazilian ZIKV strain; five of them received SOF from two to fifteen days post-infection. Both groups of dams showed ZIKV-associated clinical signals, detectable ZIKV RNA in several specimens, specific anti-ZIKV IgM and IgG antibodies, and maternal neutralizing antibodies. However, malformations occurred only among non-treated dam offspring. Compared to non-treated animals, all SOF-treated dams had a shorter ZIKV viremia and four of five neonates had undetectable ZIKV RNA in blood and tissue samples. These results support further clinical evaluations aiming for the prevention of CZS.
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Affiliation(s)
- Noemi R Gardinali
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Renato S Marchevsky
- Laboratório de Neurovirulência, Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Jaqueline M Oliveira
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Marcelo Pelajo-Machado
- Laboratório de Patologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Tatiana Kugelmeier
- Instituto de Ciência e Tecnologia em Biomodelos, Fundação Oswaldo Cruz, Avenida Brasil 4365, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Marcio P Castro
- Centro de Diagnóstico Veterinário (CEVET), Avenida Rui Barbosa 29, Niterói, RJ, Brazil
| | - Aline C A Silva
- Serviço de Equivalência e Farmacocinética (SEFAR), Vice-Presidência de Produção e Inovação em Saúde (VPPIS), Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Douglas P Pinto
- Serviço de Equivalência e Farmacocinética (SEFAR), Vice-Presidência de Produção e Inovação em Saúde (VPPIS), Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Lais B Fonseca
- Serviço de Equivalência e Farmacocinética (SEFAR), Vice-Presidência de Produção e Inovação em Saúde (VPPIS), Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Leandro S Vilhena
- Serviço de Equivalência e Farmacocinética (SEFAR), Vice-Presidência de Produção e Inovação em Saúde (VPPIS), Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Heliana M Pereira
- Serviço de Equivalência e Farmacocinética (SEFAR), Vice-Presidência de Produção e Inovação em Saúde (VPPIS), Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Sheila M B Lima
- Laboratório de Tecnologia Virológica, Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Emily H Miranda
- Laboratório de Tecnologia Virológica, Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Gisela F Trindade
- Laboratório de Tecnologia Virológica, Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - José H R Linhares
- Laboratório de Tecnologia Virológica, Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Stephanie A Silva
- Laboratório de Tecnologia Virológica, Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Juliana Gil Melgaço
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Ada M B Alves
- Laboratório de Biotecnologia e Fisiologia de Infecções Virais, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Julio Moran
- Dr. Julio Moran Laboratories, Vordergrüt 30, Herrliberg, Zurich, Switzerland
| | - Maria C C Silva
- Laboratório de Biologia Molecular de Patógenos, Centro de Ciências Naturais e Humanas, Universidade Federal Do ABC, Avenida Dos Estados, 5001, São Bernardo Do Campo, SP, Brazil
| | - Rômulo J Soares-Bezerra
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Andreza Soriano
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Gentil A Bentes
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Fernanda O Bottino
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Sarah Beatriz Salvador Castro Faria
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Rafael F Nudelman
- Instituto de Ciência e Tecnologia em Biomodelos, Fundação Oswaldo Cruz, Avenida Brasil 4365, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Claudia A A Lopes
- Instituto de Ciência e Tecnologia em Biomodelos, Fundação Oswaldo Cruz, Avenida Brasil 4365, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Javier A S Perea
- Instituto de Ciência e Tecnologia em Biomodelos, Fundação Oswaldo Cruz, Avenida Brasil 4365, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Klena Sarges
- Instituto de Ciência e Tecnologia em Biomodelos, Fundação Oswaldo Cruz, Avenida Brasil 4365, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Márcia C R Andrade
- Instituto de Ciência e Tecnologia em Biomodelos, Fundação Oswaldo Cruz, Avenida Brasil 4365, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Márcia C V A Motta
- Laboratório de Tecnologia Virológica, Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Marcos S Freire
- Laboratório de Tecnologia Virológica, Instituto de Tecnologia em Imunobiológicos Bio-Manguinhos, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Thiago M L Souza
- Instituto Nacional de Ciência e Tecnologia de Gestão da Inovação em Doenças Negligenciadas (INCT/IDN), Centro de Desenvolvimento Tecnológico Em Saúde (CDTS), Fiocruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil
| | - Jonas Schmidt-Chanasit
- WHO Collaborating Centre for Arbovirus and Haemorrhagic Fever Reference and Research, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, Hamburg, Germany
| | - Marcelo A Pinto
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Avenida Brasil, 4365, Rio de Janeiro, RJ, Brazil.
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Zhou QH, Wu FT, Pang LT, Zhang TB, Chen Z. Role of γδT cells in liver diseases and its relationship with intestinal microbiota. World J Gastroenterol 2020; 26:2559-2569. [PMID: 32523311 PMCID: PMC7265152 DOI: 10.3748/wjg.v26.i20.2559] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 04/19/2020] [Accepted: 04/28/2020] [Indexed: 02/06/2023] Open
Abstract
γδT cells are unconventional T lymphocytes that bridge innate and adaptive immunity. Based on the composition of T cell receptor and the cytokines produced, γδT cells can be divided into diverse subsets that may be present at different locations, including the liver, epithelial layer of the gut, the dermis and so on. Many of these cells perform specific functions in liver diseases, such as viral hepatitis, autoimmune liver diseases, non-alcoholic fatty liver disease, liver cirrhosis and liver cancers. In this review, we discuss the distribution, subsets, functions of γδT cells and the relationship between the microbiota and γδT cells in common hepatic diseases. As γδT cells have been used to cure hematological and solid tumors, we are interested in γδT cell-based immunotherapies to treat liver diseases.
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Affiliation(s)
- Qi-Hui Zhou
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Feng-Tian Wu
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Lan-Tian Pang
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Tian-Bao Zhang
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Zhi Chen
- Department of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
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Myeloid-derived suppressor cells exert immunosuppressive function on the T helper 2 in mice infected with Echinococcus granulosus. Exp Parasitol 2020; 215:107917. [PMID: 32446699 DOI: 10.1016/j.exppara.2020.107917] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 12/24/2019] [Accepted: 05/14/2020] [Indexed: 01/15/2023]
Abstract
Cystic echinococcosis (CE) is a worldwide hazardous zoonotic parasitosis caused by Echinococcus granulosus. CE development involves complex immunological mechanisms, including participation of multiple immune cells and effector molecules. Myeloid-derived suppressor cells (MDSCs) are known to be involved in chronic and acute inflammatory conditions. In this study, we aimed to characterize the immune function of MDSCs in CE to improve the understanding, prevention and treatment of CE. Our results indicated that MDSCs overexpressing Ly6C and Ly6G inhibit the formation and activity of T helper 2 cells in a NO-dependent manner during E. granulosus infection.
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Burwitz BJ, Hashiguchi PK, Mansouri M, Meyer C, Gilbride RM, Biswas S, Womack JL, Reed JS, Wu HL, Axthelm MK, Hansen SG, Picker LJ, Früh K, Sacha JB. MHC-E-Restricted CD8 + T Cells Target Hepatitis B Virus-Infected Human Hepatocytes. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2020; 204:2169-2176. [PMID: 32161099 PMCID: PMC8109620 DOI: 10.4049/jimmunol.1900795] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 02/05/2020] [Indexed: 12/30/2022]
Abstract
Currently 247 million people are living with chronic hepatitis B virus infection (CHB), and the development of novel curative treatments is urgently needed. Immunotherapy is an attractive approach to treat CHB, yet therapeutic approaches to augment the endogenous hepatitis B virus (HBV)-specific T cell response in CHB patients have demonstrated little success. In this study, we show that strain 68-1 rhesus macaque (RM) CMV vaccine vectors expressing HBV Ags engender HBV-specific CD8+ T cells unconventionally restricted by MHC class II and the nonclassical MHC-E molecule in RM. Surface staining of human donor and RM primary hepatocytes (PH) ex vivo revealed the majority of PH expressed MHC-E but not MHC class II. HBV-specific, MHC-E-restricted CD8+ T cells from RM vaccinated with RM CMV vaccine vectors expressing HBV Ags recognized HBV-infected PH from both human donor and RM. These results provide proof-of-concept that MHC-E-restricted CD8+ T cells could be harnessed for the treatment of CHB, either through therapeutic vaccination or adoptive immunotherapy.
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Affiliation(s)
- Benjamin J Burwitz
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
| | - Patrick K Hashiguchi
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Mandana Mansouri
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | | | - Roxanne M Gilbride
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Sreya Biswas
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Jennie L Womack
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Jason S Reed
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Helen L Wu
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
| | - Michael K Axthelm
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
| | - Scott G Hansen
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
| | - Louis J Picker
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
| | - Klaus Früh
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006;
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
| | - Jonah B Sacha
- Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006;
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006; and
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Ferrari C, Barili V, Varchetta S, Mondelli MU. Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis. THE LIVER 2020:821-850. [DOI: 10.1002/9781119436812.ch63] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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A perfect storm: fetal inflammation and the developing immune system. Pediatr Res 2020; 87:319-326. [PMID: 31537013 PMCID: PMC7875080 DOI: 10.1038/s41390-019-0582-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 08/20/2019] [Accepted: 08/23/2019] [Indexed: 12/17/2022]
Abstract
Histologic chorioamnionitis is an inflammatory disorder of the placenta that commonly precedes preterm delivery. Preterm birth related to chorioamnionitis and fetal inflammation has been associated with a risk for serious inflammatory complications in infancy. In addition, preterm infants exposed to chorioamnionitis may be more susceptible to infection in the neonatal intensive care unit and possibly later in life. A significant body of work has established an association between chorioamnionitis and inflammatory processes. However, the potential consequences of this inflammation on postnatal immunity are less understood. In this review, we will discuss current knowledge regarding the effects of fetal exposure to inflammation on postnatal immune responses.
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Chang L, Wang L, Ling N, Peng H, Chen M. Increase in liver γδ T cells with concurrent augmentation of IFN-β production during the early stages of a mouse model of acute experimental hepatitis B virus infection. Exp Ther Med 2019; 19:67-78. [PMID: 31853274 PMCID: PMC6909674 DOI: 10.3892/etm.2019.8197] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 09/27/2019] [Indexed: 12/17/2022] Open
Abstract
The role of γδ T cells in acute hepatitis B virus (HBV) infection remains unclear. For the present study, a mouse model of acute HBV infection was constructed using hydrodynamic injection-based transfection of an HBV DNA plasmid (pHBV). Subsequent changes in the percentages of γδ T cells, expression of activation molecules (CD25 and CD69) and the production of the inflammatory cytokines interferon (IFN)-γ and tumor necrosis factor-α (TNF-α) by liver γδ T cells were investigated using fluorescence-activated cell sorting (FACS). Additionally, the immune responses in the mouse liver were evaluated dynamically by measuring cytokine mRNA expression (IFN-α, IFN-β, IFN-γ or TNF-α) using reverse transcription-quantitative PCR, and other populations of immune cells, including CD4+T, CD8+T, natural killer (NK) or natural killer T (NKT) cells, using FACS. On day 1 following acute HBV infection, the percentage of liver γδ T cells was significantly increased along with the high expression of HBV markers. Additionally, liver γδ T cells displayed peak expression of the activation marker CD69 and peak IFN-γ production within this timeframe. IFN-β mRNA expression and the percentage of NK cells were elevated significantly on day 1 in liver tissues. However, there were no significant changes in the spleen or peripheral γδ T cells. Therefore, these data suggested that during the early stages of acute HBV infection, significantly increased numbers of liver γδ T cells may be involved in the enhanced immune response to the increased expression of HBV markers in the liver.
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Affiliation(s)
- Lin Chang
- Department of Clinical Laboratory, People's Hospital of Bishan District, Chongqing 402760, P.R. China
| | - Lei Wang
- Department of Clinical Laboratory, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China
| | - Ning Ling
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hui Peng
- Department of Clinical Laboratory, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, P.R. China
| | - Min Chen
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, P.R. China
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Huang XB, He YG, Zheng L, Feng H, Li YM, Li HY, Yang FX, Li J. Identification of hepatitis B virus and liver cancer bridge molecules based on functional module network. World J Gastroenterol 2019; 25:4921-4932. [PMID: 31543683 PMCID: PMC6737318 DOI: 10.3748/wjg.v25.i33.4921] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 06/29/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The potential role of chronic inflammation in the development of cancer has been widely recognized. However, there has been little research fully and thoroughly exploring the molecular link between hepatitis B virus (HBV) and hepatocellular carcinoma (HCC). AIM To elucidate the molecular links between HBV and HCC through analyzing the molecular processes of HBV-HCC using a multidimensional approach. METHODS First, maladjusted genes shared between HBV and HCC were identified by disease-related differentially expressed genes. Second, the protein-protein interaction network based on dysfunctional genes identified a series of dysfunctional modules and significant crosstalk between modules based on the hypergeometric test. In addition, key regulators were detected by pivot analysis. Finally, targeted drugs that have regulatory effects on diseases were predicted by modular methods and drug target information. RESULTS The study found that 67 genes continued to increase in the HBV-HCC process. Moreover, 366 overlapping genes in the module network participated in multiple functional blocks. It could be presumed that these genes and their interactions play an important role in the relationship between inflammation and cancer. Correspondingly, significant crosstalk constructed a module level bridge for HBV-HCC molecular processes. On the other hand, a series of non-coding RNAs and transcription factors that have potential pivot regulatory effects on HBV and HCC were identified. Among them, some of the regulators also had persistent disorders in the process of HBV-HCC including microRNA-192, microRNA-215, and microRNA-874, and early growth response 2, FOS, and Kruppel-like factor 4. Therefore, the study concluded that these pivots are the key bridge molecules outside the module. Last but not least, a variety of drugs that may have some potential pharmacological or toxic side effects on HBV-induced HCC were predicted, but their mechanisms still need to be further explored. CONCLUSION The results suggest that the persistent inflammatory environment of HBV can be utilized as an important risk factor to induce the occurrence of HCC, which is supported by molecular evidence.
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Affiliation(s)
- Xiao-Bing Huang
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Yong-Gang He
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Lu Zheng
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Huan Feng
- Division of Nursing, Second Hospital Affiliated to Third Military Medical University, Xinqiao Hospital, Chongqing 400037, China
| | - Yu-Ming Li
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Hong-Yan Li
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Feng-Xia Yang
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
| | - Jing Li
- Department of Hepatobiliary Surgery, Second Hospital Affiliated to Third Military Medical University of Xinqiao Hospital, Chongqing 400037, China
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Chen Y, Tian Z. HBV-Induced Immune Imbalance in the Development of HCC. Front Immunol 2019; 10:2048. [PMID: 31507621 PMCID: PMC6718466 DOI: 10.3389/fimmu.2019.02048] [Citation(s) in RCA: 180] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 08/13/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is one of the high-risk factors for human HCC. Despite the integration of virus DNA and the oncoprotein HBx, chronic necroinflammation and hepatocellular regeneration account for hepatocarcinogenesis. As a non-cytopathic virus, HBV is extensively recognized to mediate chronic liver damage through abnormal immune attack. However, the mechanisms driving HBV infection to HCC are poorly understood. During chronic HBV infection in humans, the adaptive immunity changes from immune tolerance to progressive immune activation, inactivation, reactivation and exhaustion, all of which may be the immune pathogenic factors for the development of HCC. Recently, the immunopathogenic mechanisms were described in mouse HBV-induced HCC models, which is absolutely dependent on the presence of HBV-specific T cell response and NK cell-derived IFN-γ, findings which are consistent with the observations from CHB and HCC patients. In this review, we summarize recent research progression on the HBV-specific CD8+ T cells, and also CD4+ T cells, B cells and non-specific immune cells and molecules underlying chronic HBV infection and eventual HCC development to demonstrate the pathogenesis of HBV-induced immune imbalance. Based on the progression, we discussed the potential of immune-based therapies and their challenges in the treatment of HBV-related HCC, including the checkpoint inhibition, genetically modified T cell transfer, therapeutic vaccines and metabolic modulation.
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Affiliation(s)
- Yongyan Chen
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Molecular Medicine, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Zhigang Tian
- Hefei National Laboratory for Physical Sciences at Microscale, The CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Molecular Medicine, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Institute of Immunology, University of Science and Technology of China, Hefei, China
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HBV Immune-Therapy: From Molecular Mechanisms to Clinical Applications. Int J Mol Sci 2019; 20:ijms20112754. [PMID: 31195619 PMCID: PMC6600394 DOI: 10.3390/ijms20112754] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/03/2019] [Accepted: 06/04/2019] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection represents a worldwide public health concern with approximately 250 million people chronically infected and at risk of developing liver cirrhosis and hepatocellular carcinoma. Nucleos(t)ide analogues (NUC) are the most widely used therapies for HBV infection, but they often require long-lasting administration to avoid the risk of HBV reactivation at withdrawal. Therefore, there is an urgent need to develop novel treatments to shorten the duration of NUC therapy by accelerating virus control, and to complement the effect of available anti-viral therapies. In chronic HBV infection, virus-specific T cells are functionally defective, and this exhaustion state is a key determinant of virus persistence. Reconstitution of an efficient anti-viral T cell response may thus represent a rational strategy to treat chronic HBV patients. In this perspective, the enhancement of adaptive immune responses by a checkpoint inhibitor blockade, specific T cell vaccines, lymphocyte metabolism targeting, and autologous T cell engineering, including chimeric antigen receptor (CAR) and TCR-redirected T cells, constitutes a promising immune modulatory approach for a therapeutic restoration of protective immunity. The advances of the emerging immune-based therapies in the setting of the HBV research field will be outlined.
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Cabrera G, Marcipar I. Vaccines and the regulatory arm of the immune system. An overview from the Trypanosoma cruzi infection model. Vaccine 2019; 37:3628-3637. [PMID: 31155420 DOI: 10.1016/j.vaccine.2019.05.015] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 04/13/2019] [Accepted: 05/03/2019] [Indexed: 01/06/2023]
Abstract
The knowledge that the immune system is composed of a regulatory/suppressor arm added a new point of view to better understand the nature of several pathologies including cancer, transplants, infections and autoimmune diseases. The striking discoveries concerning molecules and cells involved in this kind of regulation were followed by the elucidation of equally notable mechanisms used by several pathogens to manipulate the host immune system. Vaccines against pathogens are an invaluable tool developed to help the immune system cope with a potential infection or prevent disease pathology. Nowadays, there is accumulated evidence indicating that the powerful stimulation capacity of vaccines influences not only the effector arm of the immune system but also cells with regulatory/suppressor capacity, such as myeloid derived suppressor cells (MDSCs) and Foxp3+ regulatory T cells (Tregs). Trypanosoma cruzi (T. cruzi) is a protozoan parasite with a complex life cycle that has evolved several strategies to influence the regulatory immune response. Although diverse vaccine formulations have been able to stimulate the effector response, achieving non-sterilizing protection against T. cruzi, the influence of the vaccine candidates on the regulatory machinery has scarcely been assessed. This fact may not only reveal important information concerning how vaccines may influence cells with regulatory/suppressor capacity but also open the possibility to analyze whether vaccines are able to disrupt the mechanisms used by some pathogens to manipulate the host regulatory circuits. The aim of this review is to summarize and discuss available data related to the role of cellular components, like MDSCs and Foxp3+ Tregs, during T. cruzi infection, and the potential utility of those populations as additional targets for the rational design of vaccines.
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Affiliation(s)
- Gabriel Cabrera
- Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Facultad de Ciencias Médicas, Universidad Nacional del Litoral, Santa Fe, Argentina.
| | - Iván Marcipar
- Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina; Facultad de Ciencias Médicas, Universidad Nacional del Litoral, Santa Fe, Argentina
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Distinct phenotype and function of circulating Vδ1+ and Vδ2+ γδT-cells in acute and chronic hepatitis B. PLoS Pathog 2019; 15:e1007715. [PMID: 30998783 PMCID: PMC6490945 DOI: 10.1371/journal.ppat.1007715] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Revised: 04/30/2019] [Accepted: 03/19/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) persists with global and virus-specific T-cell dysfunction, without T-cell based correlates of outcomes. To determine if γδT-cells are altered in HBV infection relative to clinical status, we examined the frequency, phenotype and function of peripheral blood Vδ1+ and Vδ2+γδT-cells by multi-parameter cytometry in a clinically diverse North American cohort of chronic hepatitis B (CHB), acute hepatitis B (AHB) and uninfected control subjects. We show that circulating γδT-cells were comprised predominantly of CD3hiCD4- Vδ2+γδT-cells with frequencies that were 2–3 fold higher among Asian than non-Asian Americans and inversely correlated with age, but without differences between CHB, AHB and control subjects. However, compared to control subjects, CHB was associated with increased TbethiEomesdim phenotype in Vδ2+γδT-cells whereas AHB was associated with increased TbethiEomesdim phenotype in Vδ1+γδT-cells, with significant correlations between Tbet/Eomes expression in γδT-cells with their expression of NK and T-cell activation and regulatory markers. As for effector functions, IFNγ/TNF responses to phosphoantigens or PMA/Ionomycin in Vδ2+γδT-cells were weaker in AHB but preserved in CHB, without significant differences for Vδ1+γδT-cells. Furthermore, early IFNγ/TNF responses in Vδ2+ γδT-cells to brief PMA/Ionomycin stimulation correlated inversely with serum ALT but not HBV DNA. Accordingly, IFNγ/TNF responses in Vδ2+γδT-cells were weaker in patients with CHB with hepatitis flare compared to those without hepatitis flares, and this functional deficit persisted beyond clinical resolution of CHB flare. We conclude that circulating γδT-cells show distinct activation and differentiatiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes. We examined circulating γδT-cells in a North American cohort with chronic hepatitis B (CHB) and acute hepatitis B (AHB) compared to uninfected control subjects. While frequencies and composition of circulating γδT-cells were preserved in AHB and CHB, γδT-cells showed distinct and innate phenotypes based on the expression of Tbet/Eomes in association with various NK/T-cell markers. Notably, IFNγ/TNF responses to phosphoantigens and PMA/Ionomycin were preserved in CHB, but weaker in AHB compared to uninfected control subjects, in association with NKG2A/CD94 but not PD1. Furthermore, early IFNγ/TNF responses in Vδ2+ γδT-cells to brief PMA/Ionomycin stimulation showed significant inverse correlations with serum alanine aminotransferase, a measure of hepatocellular injury, and were persistently deficient in CHB subjects with hepatitis flare compared to those without such flares. Finally, Vδ2+ γδT-cells were significantly enriched for TbethiEomesdim phenotype in associations with their expression of NK and T-cell activation and regulatory markers, suggesting a role for Tbet in γδT-cell differentiation and function. We conclude that circulating γδT-cells show distinct activation and differentiation in acute and chronic HBV infection as part of lymphoid stress surveillance with potential role in clinical outcomes.
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50
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Yang F, Yu X, Zhou C, Mao R, Zhu M, Zhu H, Ma Z, Mitra B, Zhao G, Huang Y, Guo H, Wang B, Zhang J. Hepatitis B e antigen induces the expansion of monocytic myeloid-derived suppressor cells to dampen T-cell function in chronic hepatitis B virus infection. PLoS Pathog 2019; 15:e1007690. [PMID: 30998767 PMCID: PMC6472891 DOI: 10.1371/journal.ppat.1007690] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 03/08/2019] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is associated with functionally impaired virus-specific T cell responses. Although the myeloid-derived suppressor cells (MDSCs) are known to play a critical role in impairing antiviral T cell responses, viral factors responsible for the expansion of MDSCs in chronic hepatitis B (CHB) remain obscure. In order to elucidate the mechanism of monocytic MDSCs (mMDSCs) expansion and T cell function suppression during persistent HBV infection, we analyzed the circulation frequency of mMDSCs in 164 CHB patients and 70 healthy donors, and found that the proportion of mMDSCs in HBeAg (+) CHB patients was significantly increased compared to that in HBeAg (-) patients, which positively correlated with the level of HBeAg. Furthermore, exposure of peripheral blood mononuclear cells (PBMCs) isolated from healthy donors to HBeAg led to mMDSCs expansion and significant upregulation of IL-1β, IL-6 and indoleamine-2, 3-dioxygenase (IDO), and depletion of the cytokines abrogated HBeAg-induced mMDSCs expansion. Moreover, HBeAg-induced mMDSCs suppressed the autologous T-cell proliferation in vitro, and the purified mMDSCs from HBeAg (+) subjects markedly reduced the proliferation of CD4+ and CD8+ T cells and IFN-γ production, which could be efficiently restored by inhibiting IDO. In summary, HBeAg-induced mMDSCs expansion impairs T cell function through IDO pathway and favors the establishment of a persistent HBV infection, suggesting a mechanism behind the development of HBeAg-induced immune tolerance. HBeAg is not a structural component of HBV and is not essential for viral DNA replication, however, HBeAg positivity is associated with high levels of viremia in patients. HBeAg may represent a viral strategy to establish persistent infection, but the mechanism remains largely ambiguous. Growing evidence suggests that chronic HBV infection may be shaped by MDSCs-mediated T-cell exhaustion. Here, we report that the frequency of circulating mMDSCs in HBeAg (+) patients is higher than HBeAg (-) patients and positively correlates with serum HBeAg levels. The correlation is further demonstrated by in vitro HBeAg stimulation of PBMCs, which induced mMDSCs expansion. Furthermore, HBeAg-induced expansion of mMDSCs is dependent upon cytokine IL-6 and IL-1β, and the indoleamine-2, 3-dioxynase (IDO) plays a critical role in the suppression of T cell proliferation and IFN-γ production by HBeAg-activated mMDSCs. Therefore, our findings demonstrate a novel mechanism responsible for mMDSCs expansion in HBeAg (+) patients, and suggest that the HBeAg-mMDSC-IDO axis may serve as an immunotherapeutic target of chronic hepatitis B.
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Affiliation(s)
- Feifei Yang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Xueping Yu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Chenliang Zhou
- Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Richeng Mao
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Mengqi Zhu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Haoxiang Zhu
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhenxuan Ma
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Bidisha Mitra
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
| | - Gan Zhao
- Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
| | - Haitao Guo
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
- * E-mail: (HG); (BW); (JZ)
| | - Bin Wang
- Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, China
- * E-mail: (HG); (BW); (JZ)
| | - Jiming Zhang
- Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China
- Key Laboratory of Medical Molecular Virology of the Ministry of Health and Ministry of Education, School of Basic Medical Sciences, Fudan University, Shanghai, China
- * E-mail: (HG); (BW); (JZ)
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