|
1
|
Jing ZL, Liu GL, Zhou N, Xu DY, Feng N, Lei Y, Ma LL, Tang MS, Tong GH, Tang N, Deng YJ. Interferon-γ in the tumor microenvironment promotes the expression of B7H4 in colorectal cancer cells, thereby inhibiting cytotoxic T cells. Sci Rep 2024; 14:6053. [PMID: 38480774 PMCID: PMC10937991 DOI: 10.1038/s41598-024-56681-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 03/09/2024] [Indexed: 03/17/2024] Open
Abstract
The bioactivity of interferon-γ (IFN-γ) in cancer cells in the tumor microenvironment (TME) is not well understood in the current immunotherapy era. We found that IFN-γ has an immunosuppressive effect on colorectal cancer (CRC) cells. The tumor volume in immunocompetent mice was significantly increased after subcutaneous implantation of murine CRC cells followed by IFN-γ stimulation, and RNA sequencing showed high expression of B7 homologous protein 4 (B7H4) in these tumors. B7H4 promotes CRC cell growth by inhibiting the release of granzyme B (GzmB) from CD8+ T cells and accelerating apoptosis in CD8+ T cells. Furthermore, interferon regulatory factor 1 (IRF1), which binds to the B7H4 promoter, is positively associated with IFN-γ stimulation-induced expression of B7H4. The clinical outcome of patients with CRC was negatively related to the high expression of B7H4 in cancer cells or low expression of CD8 in the microenvironment. Therefore, B7H4 is a biomarker of poor prognosis in CRC patients, and interference with the IFN-γ/IRF1/B7H4 axis might be a novel immunotherapeutic method to restore the cytotoxic killing of CRC cells.
Collapse
Affiliation(s)
- Zhi-Liang Jing
- Department of Pathology, School of Basic Medical Sciences and Nan Fang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, China
- Department of Pathology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, China
| | - Guang-Long Liu
- Department of Pathology, School of Basic Medical Sciences and Nan Fang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, China
| | - Na Zhou
- Department of Pathology, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou, 510120, China
| | - Dong-Yan Xu
- Department of Pathology, School of Basic Medical Sciences and Nan Fang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, China
| | - Na Feng
- Department of Pathology, Dongguan Songshan Lake Tungwah Hospital, Dongguan, 523413, China
| | - Yan Lei
- Department of Pathology, School of Basic Medical Sciences and Nan Fang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, China
| | - Li-Li Ma
- Department of Pathology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, 510080, China
| | - Min-Shan Tang
- Department of Pathology, School of Basic Medical Sciences and Nan Fang Hospital, Southern Medical University, Guangzhou, 510515, China
- Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, China
| | - Gui-Hui Tong
- Department of Pathology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510415, China
| | - Na Tang
- Department of Pathology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, China.
| | - Yong-Jian Deng
- Department of Pathology, School of Basic Medical Sciences and Nan Fang Hospital, Southern Medical University, Guangzhou, 510515, China.
- Guangdong Provincial Key Laboratory of Molecular Tumor Pathology, Guangzhou, 510515, China.
| |
Collapse
|
|
2
|
Erratum: Type 1 regulatory T cell-mediated tolerance in health and disease. Front Immunol 2023; 13:1125497. [PMID: 36761160 PMCID: PMC9903213 DOI: 10.3389/fimmu.2022.1125497] [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: 12/16/2022] [Accepted: 12/16/2022] [Indexed: 01/26/2023] Open
Abstract
[This corrects the article .].
Collapse
|
|
3
|
Park SJ, Hahn YS. Hepatocytes infected with hepatitis C virus change immunological features in the liver microenvironment. Clin Mol Hepatol 2023; 29:65-76. [PMID: 35957546 PMCID: PMC9845665 DOI: 10.3350/cmh.2022.0032] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Accepted: 08/11/2022] [Indexed: 02/02/2023] Open
Abstract
Hepatitis C virus (HCV) infection is remarkably efficient in establishing viral persistence, leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC). Direct-acting antiviral agents (DAAs) are promising HCV therapies to clear the virus. However, recent reports indicate potential increased risk of HCC development among HCV patients with cirrhosis following DAA therapy. CD8+ T-cells participate in controlling HCV infection. However, in chronic hepatitis C patients, severe CD4+ and CD8+ T-cell dysfunctions have been observed. This suggests that HCV may employ mechanisms to counteract or suppress the host T-cell responses. The primary site of viral replication is within hepatocytes where infection can trigger the expression of costimulatory molecules and the secretion of immunoregulatory cytokines. Numerous studies indicate that HCV infection in hepatocytes impairs antiviral host immunity by modulating the expression of immunoregulatory molecules. Hepatocytes expressing whole HCV proteins upregulate the ligands of programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and transforming growth factor β (TGF-β) synthesis compared to those in hepatocytes in the absence of the HCV genome. Importantly, HCV-infected hepatocytes are capable of inducing regulatory CD4+ T-cells, releasing exosomes displaying TGF-β on exosome surfaces, and generating follicular regulatory T-cells. Recent studies report that the expression profile of exosome microRNAs provides biomarkers of HCV infection and HCV-related chronic liver diseases. A better understanding of the immunoregulatory mechanisms and identification of biomarkers associated with HCV infection will provide insight into designing vaccine against HCV to bypass HCV-induced immune dysregulation and prevent development of HCV-associated chronic liver diseases.
Collapse
Affiliation(s)
- Soo-Jeung Park
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA
| | - Young S. Hahn
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA,USA,Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA,Corresponding author : Young S. Hahn Department of Microbiology, Immunology and Cancer Biology, University of Virginia, 345 Crispell Dr, Charlottesville, VA 22908, USA Tel: +1-434-924-1275, Fax: +1-434-924-1221, E-mail:
| |
Collapse
|
|
4
|
Freeborn RA, Strubbe S, Roncarolo MG. Type 1 regulatory T cell-mediated tolerance in health and disease. Front Immunol 2022; 13:1032575. [PMID: 36389662 PMCID: PMC9650496 DOI: 10.3389/fimmu.2022.1032575] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/10/2022] [Indexed: 09/02/2023] Open
Abstract
Type 1 regulatory T (Tr1) cells, in addition to other regulatory cells, contribute to immunological tolerance to prevent autoimmunity and excessive inflammation. Tr1 cells arise in the periphery upon antigen stimulation in the presence of tolerogenic antigen presenting cells and secrete large amounts of the immunosuppressive cytokine IL-10. The protective role of Tr1 cells in autoimmune diseases and inflammatory bowel disease has been well established, and this led to the exploration of this population as a potential cell therapy. On the other hand, the role of Tr1 cells in infectious disease is not well characterized, thus raising concern that these tolerogenic cells may cause general immune suppression which would prevent pathogen clearance. In this review, we summarize current literature surrounding Tr1-mediated tolerance and its role in health and disease settings including autoimmunity, inflammatory bowel disease, and infectious diseases.
Collapse
Affiliation(s)
- Robert A. Freeborn
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, United States
| | - Steven Strubbe
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, United States
| | - Maria Grazia Roncarolo
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford School of Medicine, Stanford, CA, United States
- Institute for Stem Cell Biology and Regenerative Medicine (ISCBRM), Stanford School of Medicine, Stanford, CA, United States
- Center for Definitive and Curative Medicine (CDCM), Stanford School of Medicine, Stanford, CA, United States
| |
Collapse
|
|
5
|
Vallejos-Vidal E, Reyes-López FE, Sandino AM, Imarai M. Sleeping With the Enemy? The Current Knowledge of Piscine Orthoreovirus (PRV) Immune Response Elicited to Counteract Infection. Front Immunol 2022; 13:768621. [PMID: 35464421 PMCID: PMC9019227 DOI: 10.3389/fimmu.2022.768621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 02/25/2022] [Indexed: 11/13/2022] Open
Abstract
Piscine orthoreovirus (PRV) is a virus in the genus Orthoreovirus of the Reoviridae family, first described in 2010 associated with Heart and Skeletal Muscle Inflammation (HSMI) in Atlantic salmon (Salmo salar). Three phases of PRV infection have been described, the early entry and dissemination, the acute dissemination phase, and the persistence phase. Depending on the PRV genotype and the host, infection can last for life. Mechanisms of immune response to PRV infection have been just beginning to be studied and the knowledge in this matter is here revised. PRV induces a classical antiviral immune response in experimental infection of salmonid erythrocytes, including transcriptional upregulation of ifn-α, rig-i, mx, and pkr. In addition, transcript upregulation of tcra, tcrb, cd2, il-2, cd4-1, ifn-γ, il-12, and il-18 has been observed in Atlantic salmon infected with PRV, indicating that PRV elicited a Th1 type response probably as a host defense strategy. The high expression levels of cd8a, cd8b, and granzyme-A in PRV-infected fish suggest a positive modulatory effect on the CTL-mediated immune response. This is consistent with PRV-dependent upregulation of the genes involved in antigen presentation, including MHC class I, transporters, and proteasome components. We also review the potential immune mechanisms associated with the persistence phenotype of PRV-infected fish and its consequence for the development of a secondary infection. In this scenario, the application of a vaccination strategy is an urgent and challenging task due to the emergence of this viral infection that threatens salmon farming.
Collapse
Affiliation(s)
- Eva Vallejos-Vidal
- Centro de Biotecnología Acuícola, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile.,Facultad de Medicina Veterinaria y Agronomía, Universidad de Las Américas, Santiago, Chile
| | - Felipe E Reyes-López
- Centro de Biotecnología Acuícola, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile.,Department of Cell Biology, Physiology, and Immunology, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Ana María Sandino
- Centro de Biotecnología Acuícola, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile.,Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Mónica Imarai
- Centro de Biotecnología Acuícola, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile.,Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| |
Collapse
|
|
6
|
Sugrue JA, O’Farrelly C. Uncovering Resistance to Hepatitis C Virus Infection: Scientific Contributions and Unanswered Questions in the Irish Anti-D Cohort. Pathogens 2022; 11:pathogens11030306. [PMID: 35335630 PMCID: PMC8953313 DOI: 10.3390/pathogens11030306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/20/2022] [Accepted: 02/24/2022] [Indexed: 02/04/2023] Open
Abstract
Infections caused inadvertently during clinical intervention provide valuable insight into the spectrum of human responses to viruses. Delivery of hepatitis C virus (HCV)-contaminated blood products in the 70s (before HCV was identified) have dramatically increased our understanding of the natural history of HCV infection and the role that host immunity plays in the outcome to viral infection. In Ireland, HCV-contaminated anti-D immunoglobulin (Ig) preparations were administered to approximately 1700 pregnant Irish rhesus-negative women in 1977–1979. Though tragic in nature, this outbreak (alongside a smaller episode in 1993) has provided unique insight into the host factors that influence outcomes after HCV exposure and the subsequent development of disease in an otherwise healthy female population. Despite exposure to highly infectious batches of anti-D, almost 600 of the HCV-exposed women have never shown any evidence of infection (remaining negative for both viral RNA and anti-HCV antibodies). Detailed analysis of these individuals may shed light on innate immune pathways that effectively block HCV infection and potentially inform us more generally about the mechanisms that contribute to viral resistance in human populations.
Collapse
Affiliation(s)
- Jamie A. Sugrue
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02R590 Dublin, Ireland
- Correspondence: (J.A.S.); (C.O.)
| | - Cliona O’Farrelly
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, D02R590 Dublin, Ireland
- School of Medicine, Trinity College Dublin, D02R590 Dublin, Ireland
- Correspondence: (J.A.S.); (C.O.)
| |
Collapse
|
|
7
|
Aghabi YO, Yasin A, Kennedy JI, Davies SP, Butler AE, Stamataki Z. Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer. Front Immunol 2021; 12:662134. [PMID: 33953725 PMCID: PMC8089374 DOI: 10.3389/fimmu.2021.662134] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 03/22/2021] [Indexed: 12/14/2022] Open
Abstract
Persistent liver inflammation can lead to cirrhosis, which associates with significant morbidity and mortality worldwide. There are no curative treatments beyond transplantation, followed by long-term immunosuppression. The global burden of end stage liver disease has been increasing and there is a shortage of donor organs, therefore new therapies are desperately needed. Harnessing the power of the immune system has shown promise in certain autoimmunity and cancer settings. In the context of the liver, regulatory T cell (Treg) therapies are in development. The hypothesis is that these specialized lymphocytes that dampen inflammation may reduce liver injury in patients with chronic, progressive diseases, and promote transplant tolerance. Various strategies including intrinsic and extracorporeal expansion of Treg cells, aim to increase their abundance to suppress immune responses. We recently discovered that hepatocytes engulf and delete Treg cells by enclysis. Herein, we propose that inhibition of enclysis may potentiate existing regulatory T cell therapeutic approaches in patients with autoimmune liver diseases and in patients receiving a transplant. Moreover, in settings where the abundance of Treg cells could hinder beneficial immunity, such us in chronic viral infection or liver cancer, enhancement of enclysis could result in transient, localized reduction of Treg cell numbers and tip the balance towards antiviral and anti-tumor immunity. We describe enclysis as is a natural process of liver immune regulation that lends itself to therapeutic targeting, particularly in combination with current Treg cell approaches.
Collapse
Affiliation(s)
| | | | | | | | | | - Zania Stamataki
- College of Medical and Dental Sciences, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| |
Collapse
|
|
8
|
Rahimzadeh M, Naderi N. Toward an understanding of regulatory T cells in COVID-19: A systematic review. J Med Virol 2021; 93:4167-4181. [PMID: 33605463 DOI: 10.1002/jmv.26891] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 02/12/2021] [Accepted: 02/16/2021] [Indexed: 12/12/2022]
Abstract
A more detailed understanding of Treg cells in COVID-19 infection will broaden our knowledge of the COVID-19 immunopathology and give us more insight into the curative immune-based strategies. We systematically searched electronic databases (PubMed, Google Scholar, EMBASE) and identified 18 eligible studies. Despite the inconsistencies between the results, we observed a trend toward decreasing Treg levels in severe COVID-19 patients. This finding underlines the hypothesis that Tregs play a role in the pathogenesis of COVID-19. Further studies on Tregs' functional aspects are necessary to illustrate Tregs' potential role in COVID-19 disease.
Collapse
Affiliation(s)
- Mahsa Rahimzadeh
- Infectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Nadereh Naderi
- Department of Immunology, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| |
Collapse
|
|
9
|
Kervevan J, Chakrabarti LA. Role of CD4+ T Cells in the Control of Viral Infections: Recent Advances and Open Questions. Int J Mol Sci 2021; 22:E523. [PMID: 33430234 PMCID: PMC7825705 DOI: 10.3390/ijms22020523] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 12/23/2020] [Accepted: 12/30/2020] [Indexed: 12/26/2022] Open
Abstract
CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral infections. In this review, we present recent advances in understanding the nature of CD4+ T cell help provided to antiviral effectors. Drawing from our studies of natural human immunodeficiency virus (HIV) control, we then focus on the role of high-affinity T cell receptor (TCR) clonotypes in mediating antiviral CD4+ T cell responses. Last, we discuss the role of TCR affinity in determining CD4+ T cell differentiation, reviewing the at times divergent studies associating TCR signal strength to the choice of a T helper 1 (Th1) or a T follicular helper (Tfh) cell fate.
Collapse
Affiliation(s)
- Jérôme Kervevan
- Control of Chronic Viral Infections Group (CIVIC), Virus and Immunity Unit, Institut Pasteur, 75724 Paris, France;
- CNRS UMR, 3569 Paris, France
| | - Lisa A. Chakrabarti
- Control of Chronic Viral Infections Group (CIVIC), Virus and Immunity Unit, Institut Pasteur, 75724 Paris, France;
- CNRS UMR, 3569 Paris, France
| |
Collapse
|
|
10
|
McGee MC, August A, Huang W. TCR/ITK Signaling in Type 1 Regulatory T cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:115-124. [PMID: 33523446 DOI: 10.1007/978-981-15-6407-9_7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Type 1 regulatory T (Tr1) cells can modulate inflammation through multiple direct and indirect molecular and cellular mechanisms and have demonstrated potential for anti-inflammatory therapies. Tr1 cells do not express the master transcription factor of conventional regulatory T cells, Foxp3, but express high levels of the immunomodulatory cytokine, IL-10. IL-2-inducible T-cell kinase (ITK) is conserved between mouse and human and is highly expressed in T cells. ITK signaling downstream of the T-cell receptor (TCR) is critical for T-cell subset differentiation and function. Upon activation by TCR, ITK is critical for Ras activation, leading to downstream activation of MAPKs and upregulation of IRF4, which further enable Tr1 cell differentiation and suppressive function. We summarize here the structure, signaling pathway, and function of ITK in T-cell lineage designation, with an emphasis on Tr1 cell development and function.
Collapse
Affiliation(s)
- Michael C McGee
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA
| | - Avery August
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Weishan Huang
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA. .,Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
| |
Collapse
|
|
11
|
Amoras EDSG, Monteiro Gomes ST, Freitas Queiroz MA, de Araújo MSM, de Araújo MTF, da Silva Conde SRS, Ishak R, Vallinoto ACR. Intrahepatic interleukin 10 expression modulates fibrinogenesis during chronic HCV infection. PLoS One 2020; 15:e0241199. [PMID: 33125400 PMCID: PMC7598451 DOI: 10.1371/journal.pone.0241199] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 10/10/2020] [Indexed: 12/17/2022] Open
Abstract
Introduction Liver fibrosis is a result of continuous damage to the liver combined with accumulation of the extracellular matrix and is characteristic of most chronic liver diseases such as hepatitis C virus (HCV) infection. Methods This study evaluated interleukin 10 (IL10) expression in the liver and plasma of 45 HCV patients and its association with the pathogenesis and progression of liver fibrosis. The expression of transforming growth factor beta (TGFB1) was also assessed. Patients were divided into three groups according to the METAVIR classification (F0-F1, F2 and F3-F4); there was also a control group (n = 8). Results In the control group, high intrahepatic IL10 mRNA expression showed a positive association with F0-F1 fibrosis, no inflammation, low concentrations of liver enzymes and a high viral load; conversely, low intrahepatic IL10 mRNA expression showed a negative association with fibrosis progression. Intrahepatic TGFB1 mRNA expression was greater in the HCV group than in the control group, and regarding different disease phases, its expression increased as fibrosis evolved to more severe forms. Conclusion Intrahepatic IL10 mRNA expression decreases with persistent fibrosis, probably due to the production of TGF-β1, a potent antimitotic and fibrogenic cytokine. IL10 restricts and decreases the immune response and limits the fibrogenic response; however, a decrease in IL10 favors persistent inflammatory infiltrate, resulting in severe fibrosis.
Collapse
Affiliation(s)
| | | | | | | | | | - Simone Regina Souza da Silva Conde
- School of Medicine, Health Science Institute, Universidade Federal do Pará, Belém, Pará, Brazil
- Hepatology Outpatient Clinic, João Barros Barreto University Hospital, Belém, Pará, Brazil
| | - Ricardo Ishak
- Virology Laboratory, Biological Science Institute, Federal University of Pará, Belém, Pará, Brazil
| | | |
Collapse
|
|
12
|
Inflammation During Virus Infection: Swings and Roundabouts. DYNAMICS OF IMMUNE ACTIVATION IN VIRAL DISEASES 2020. [PMCID: PMC7121364 DOI: 10.1007/978-981-15-1045-8_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Inflammation constitutes a concerted series of cellular and molecular responses that follow disturbance of systemic homeostasis, by either toxins or infectious organisms. Leukocytes modulate inflammation through production of secretory mediators, like cytokines and chemokines, which work in an autocrine and/or paracrine manner. These mediators can either promote or attenuate the inflammatory response and depending on differential temporal and spatial expression play a crucial role in the outcome of infection. Even though the objective is clearance of the pathogen with minimum damage to host, the pathogenesis of multiple human pathogenic viruses has been suggested to emanate from a dysregulation of the inflammatory response, sometimes with fatal consequences. This review discusses the nature and the outcome of inflammatory response, which is triggered in the human host subsequent to infection by single-sense plus-strand RNA viruses. In view of such harmful effects of a dysregulated inflammatory response, an exogenous regulation of these reactions by either interference or supplementation of critical regulators has been suggested. Currently multiple such factors are being tested for their beneficial and adverse effects. A successful use of such an approach in diseases of viral etiology can potentially protect the affected individual without directly affecting the virus life cycle. Further, such approaches whenever applicable would be useful in mitigating death and/or debility that is caused by the infection of those viruses which have proven particularly difficult to control by either prophylactic vaccines and/or therapeutic strategies using specific antiviral drugs.
Collapse
|
|
13
|
Ghazal K, Morales O, Barjon C, Dahlqvist G, Aoudjehane L, Ouaguia L, Delhem N, Conti F. Early high levels of regulatory T cells and T helper 1 may predict the progression of recurrent hepatitis C after liver transplantation. Clin Res Hepatol Gastroenterol 2019; 43:273-281. [PMID: 30713032 DOI: 10.1016/j.clinre.2018.10.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 09/25/2018] [Accepted: 10/02/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND Immune response failure against hepatitis C virus (HCV) has been associated with an increased regulatory T cell (Treg) activity. After liver transplantation (LT), 80% of patients experience an accelerated progression of hepatitis C recurrence. The aim of this work was to assess the involvement of Tregs, T helper (Th) 1, 2 and 17 cells in recurrent hepatitis C. METHODS Peripheral blood cells obtained before and one month after LT from 22 recipients were analysed. Forty-four key molecules related to Treg, Th1, 2 and 17 responses, were evaluated using qRT-PCR. Liver recipients were classified in two groups according to graft fibrosis evaluated by the METAVIR score on the biopsy performed one year after LT (mild: F ≤ 1, n = 13; severe: F > 1, n = 9). Patients developing a severe recurrence were compared with patients with a mild recurrence. RESULTS mRNA levels of Treg markers obtained one month after LT were significantly increased in patients with a severe disease course when compared to patients with a mild recurrence. Markers of the Th1 response were elevated in the same group. No differences in the markers determined before LT were observed. CONCLUSION These findings suggest that Treg, induced by a multifactorial process, which could include a strong Th1 response itself, may play a role in suppressing the early antiviral response, leading to a severe recurrence of hepatitis C.
Collapse
Affiliation(s)
- K Ghazal
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Saint-Antoine Research Center, 75012 Paris, France; AP-HP, Bicêtre Hospital, Biochemistry Laboratory, 94275 Le Kremlin-Bicêtre cedex, France.
| | - O Morales
- CNRS, UMR8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR 142, 59021 Lille cedex, France
| | - C Barjon
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Saint-Antoine Research Center, 75012 Paris, France; De Duve Institute, Université catholique de Louvain, 1200 Brussels, Belgium
| | - G Dahlqvist
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Saint-Antoine Research Center, 75012 Paris, France; Cliniques Universitaires Saint-Luc, 1200 Woluwe-Saint-Lambert, Belgium
| | - L Aoudjehane
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Saint-Antoine Research Center, 75012 Paris, France; Institute of Cardiometabolism and Nutrition (ICAN), 75013 Paris, France
| | - L Ouaguia
- CNRS, UMR8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR 142, 59021 Lille cedex, France
| | - N Delhem
- CNRS, UMR8161, Institut de Biologie de Lille, Université de Lille, Institut Pasteur de Lille, IFR 142, 59021 Lille cedex, France
| | - F Conti
- Sorbonne Universités, UPMC Université Paris 06, INSERM, UMR_S 938, Saint-Antoine Research Center, 75012 Paris, France; AP-HP, Pitié-Salpêtrière hospital, Unité Médicale de Transplantation Hépatique, 75013 Paris, France
| |
Collapse
|
|
14
|
Villani R, Vendemiale G, Serviddio G. Molecular Mechanisms Involved in HCC Recurrence after Direct-Acting Antiviral Therapy. Int J Mol Sci 2018; 20:ijms20010049. [PMID: 30583555 PMCID: PMC6337751 DOI: 10.3390/ijms20010049] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 12/18/2018] [Accepted: 12/19/2018] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis C is associated with a high risk of developing hepatocellular carcinoma (HCC) because of a direct effect of the Hepatitis C Virus (HCV) proteins and an indirect oncogenic effect of chronic inflammation and impaired immune response. The treatment of chronic hepatitis C markedly reduces all-cause mortality; in fact, interferon-based treatment has shown a reduction of HCC incidence of more than 70%. The recent introduction of the highly effective direct-acting antivirals (DAAs) has completely changed the scenario of chronic hepatitis C (CHC) with rates of HCV cure over 90%. However, an unexpectedly high incidence of HCC recurrence was observed in patients after DAA treatment (27% versus 0.4–2% in patients who received interferon treatment). The mechanism that underlies the high rate of tumor relapse is currently unknown and is one of the main issues in hepatology. We reviewed the possible mechanisms involved in HCC recurrence after DAA treatment.
Collapse
MESH Headings
- Animals
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/epidemiology
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/virology
- Hepacivirus/drug effects
- Hepacivirus/immunology
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/virology
- Humans
- Incidence
- Interferons/therapeutic use
- Liver Neoplasms/drug therapy
- Liver Neoplasms/epidemiology
- Liver Neoplasms/immunology
- Liver Neoplasms/virology
- Macrophages/drug effects
- Monocytes/drug effects
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/immunology
- Neoplasm Recurrence, Local/virology
- Neutrophils/drug effects
Collapse
Affiliation(s)
- Rosanna Villani
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gianluigi Vendemiale
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| | - Gaetano Serviddio
- C.U.R.E. University Centre for Liver Disease Research and Treatment, Department of Medical and Surgical Sciences, Institute of Internal Medicine, University of Foggia, 71122 Foggia, Italy.
| |
Collapse
|
|
15
|
The Biology of T Regulatory Type 1 Cells and Their Therapeutic Application in Immune-Mediated Diseases. Immunity 2018; 49:1004-1019. [DOI: 10.1016/j.immuni.2018.12.001] [Citation(s) in RCA: 153] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 11/25/2018] [Accepted: 11/30/2018] [Indexed: 12/14/2022]
|
|
16
|
Nafady A, Nafady-Hego H, Abdelwahab NM, Eltellawy RHN, Abu Faddan NH. Peripheral lymphocytes analyses in children with chronic hepatitis C virus infection. Eur J Clin Invest 2018; 48:e13004. [PMID: 30022474 DOI: 10.1111/eci.13004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2017] [Revised: 05/24/2018] [Accepted: 07/16/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Hepatitis C virus (HCV)-specific immune response is believed to play a crucial role in viral clearance. There is, nevertheless, no reliable parameter to monitor this immune response or predict chronic HCV infection development. METHOD An observational case-control study was performed to identify such parameters, peripheral blood mononuclear cells from 57 children with chronic HCV were systemically phenotyped, and the serum level of Interferon gamma and interleukin (IL) -17 was measured. The data were compared with 37 age-matched healthy volunteers (controls). RESULTS Children with chronic HCV infection had a lower frequency of natural killer cells (NK) cells, CD56Dim NK cells and expansion of CD56Bright NK cells compared with controls (P = 0.001, P < 0.0001 and P < 0.0001 respectively). Increased CD56Dim NK cells were negatively correlated with the higher viral load, R2 = 0.29, P = 0.05, while, increased NK T cells were positively correlated with high viral load, R2 = 0.17, P = 0.011. T helper cells, naive T cells, CD127 negative T cells, and HLA-DR-positive T cells significantly increased in patients than in controls. The frequency of CD4+CD25high+ T regulatory (Treg) cells increased in HCV-infected patients, compared with those in control, and FOXP3 was upregulated within them. Treg cells' increase was positively correlated with high viral load, R2 = 0.45, P = 0.004. The level of IL-17 was higher in HCV patients than that in control, P < 0.0001. CONCLUSION Although the contribution of those markers to the chronic HCV establishment in children remains elusive, the results may provide important clues for reliable indicators of HCV infection.
Collapse
Affiliation(s)
- Asmaa Nafady
- Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Department of Clinical and Chemical Pathology, Faculty of Medicine, South Valley University, Qena, Egypt
| | - Hanaa Nafady-Hego
- Microbiology and Immunology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nadia M Abdelwahab
- Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Radwa H N Eltellawy
- Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nagla H Abu Faddan
- Department of Pediatrics, children hospital, Faculty of Medicine, Assiut University, Assiut, Egypt
| |
Collapse
|
|
17
|
Fan R, Yao H, Cao C, Zhao X, Khalid A, Zhao J, Zhang Z, Xu S. Gene Silencing of Selenoprotein K Induces Inflammatory Response and Activates Heat Shock Proteins Expression in Chicken Myoblasts. Biol Trace Elem Res 2017; 180:135-145. [PMID: 28281222 DOI: 10.1007/s12011-017-0979-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 02/20/2017] [Indexed: 12/24/2022]
Abstract
In the present study, specific small interfering RNA (siRNA) for selenoprotein K (Selk) gene was designed and transfected into chicken myoblasts. Then, the expressions of inflammatory factors (including induced nitric oxide synthase [iNOS], nuclear factor-kappa B [NF-κB], heme-oxygenase-1 [HO-1], cyclooxygenase-2 [COX-2], and prostaglandin E synthase [PTGEs]), inflammation-related cytokines (including interleukin [IL]-1β, IL-6, IL-7, IL-8, IL-17, and interferon [IFN]-γ), and heat shock proteins (HSPs) (including HSP27, HSP40, HSP60, HSP70, and HSP90) were examined at 24 and 72 h after transfection. The results showed that messenger RNA (mRNA) expressions of iNOS, NF-κB, HO-1, COX-2, IL-6, IL-7, IL-8, HSP 27, HSP 40, HSP 60, HSP 70, and HSP 90 were significantly increased (p < 0.05) at 24 and 72 h after siRNA transfection, and the mRNA expressions of PTGEs, IL-1β, IL-17, and IFN-γ were significantly increased and decreased (p < 0.05) at 24 and 72 h after siRNA transfection. The results also showed that the protein expressions of iNOS, NF-κB, HO-1, COX-2, HSP60, HSP70, and HSP90 were significantly increased (p < 0.05) at 24 and 72 h after siRNA transfection. The correlation analysis and principal component analysis (PCA) showed that PTGEs, IL-1β, IL-17, IFN-γ, HSP40, and HSP90 might play special roles in response to Selk silencing in chicken myoblasts. These results indicated that Selk silencing induced inflammation response by affecting the expression levels of inflammatory factors and inflammation-related cytokines, and the heat shock proteins might play protective roles in this response in chicken myoblasts.
Collapse
Affiliation(s)
- Ruifeng Fan
- Department of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Haidong Yao
- Department of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Changyu Cao
- Department of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Xia Zhao
- Department of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Ahmed Khalid
- Department of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Jinxin Zhao
- Department of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China
| | - Ziwei Zhang
- Department of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
| | - Shiwen Xu
- Department of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, People's Republic of China.
| |
Collapse
|
|
18
|
Sehrawat S, Rouse BT. Interplay of Regulatory T Cell and Th17 Cells during Infectious Diseases in Humans and Animals. Front Immunol 2017; 8:341. [PMID: 28421070 PMCID: PMC5377923 DOI: 10.3389/fimmu.2017.00341] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 03/09/2017] [Indexed: 12/14/2022] Open
Abstract
It is now clear that the outcome of an inflammatory process caused by infections depends on the balance of responses by several components of the immune system. Of particular relevance is the interplay between regulatory T cells (Tregs) and CD4+ T cells that produce IL-17 (Th17 cells) during immunoinflammatory events. In addition to discussing studies done in mice to highlight some unresolved issues in the biology of these cells, we emphasize the need to include outbred animals and humans in analyses. Achieving a balance between Treg and Th17 cells responses represents a powerful approach to control events during immunity and immunopathology.
Collapse
Affiliation(s)
- Sharvan Sehrawat
- Indian Institute of Science Education and Research Mohali, Mohali, Punjab, India
| | - Barry T Rouse
- Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, The University of Tennessee, Knoxville, TN, USA
| |
Collapse
|
|
19
|
Hetta HF, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, Medhat A, Nassar MI, Sherman KE, Shata MTM. Extra-hepatic infection of hepatitis C virus in the colon tissue and its relationship with hepatitis C virus pathogenesis. J Med Microbiol 2016; 65:703-712. [PMID: 27166142 DOI: 10.1099/jmm.0.000272] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Extra-hepatic compartments might contribute to hepatitis C virus (HCV) persistence and extra-hepatic manifestations. Therefore, we investigated HCV infection in colonic tissue in patients with chronic hepatitis C (CHC) and its relationship with HCV pathogenesis. Colonic biopsies were collected from three groups with CHC infection: treatment naïve (TN; n=12), non-responders (NR; n=10) to anti-HCV therapy (pegylated interferon-α and ribavirin) and sustained virologic response (SVR; n=10) and from a fourth healthy control group (n=10). Liver biopsies were examined to assess inflammation and fibrosis. HCV infection and colonic T regulatory (Treg) frequency were detected by immunohistochemistry. HCV core and NS3 proteins were detected in B cells and macrophage/monocytes of 42 % and 25 % of TN and 50 % and 30 % of NR, respectively, but not in SVR or control group. The numbers of cells expressing HCV proteins were positively correlated with both HCV viral load and colonic Treg frequency. A significant negative correlation between HCV-expressing cells with both liver inflammation and fibrosis was identified. Our study provides evidence that HCV can infect B cells and macrophages of the colon. The correlations between HCV infection in colonic tissue and HCV viral load and liver pathology underline the significance of this extra-hepatic infection in HCV pathogenesis and response to therapy.
Collapse
Affiliation(s)
- Helal F Hetta
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A Mekky
- Department of Gastroenterology & Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nasr K Khalil
- Assiut Liver Institute for Treatment of Hepatitis C, Assiut, Egypt
| | - Wegdan A Mohamed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Feky
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Shabaan H Ahmed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Enas A Daef
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ahmed Medhat
- Department of Gastroenterology & Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud I Nassar
- Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Kenneth E Sherman
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
| | - Mohamed Tarek M Shata
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, OH, USA
| |
Collapse
|
|
20
|
Sheiko MA, Rosen HR. Hepatic Fibrosis in Hepatitis C. HEPATITIS C VIRUS II 2016:79-108. [DOI: 10.1007/978-4-431-56101-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
21
|
Serum level of interleukin-8 and interleukin-10 as predictors for response to interferon–ribavirin combined therapy. EGYPTIAN LIVER JOURNAL 2016. [DOI: 10.1097/01.elx.0000481902.94221.61] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
|
|
22
|
Abstract
Despite advances in therapy, hepatitis C virus infection remains a major global health issue with 3 to 4 million incident cases and 170 million prevalent chronic infections. Complex, partially understood, host-virus interactions determine whether an acute infection with hepatitis C resolves, as occurs in approximately 30% of cases, or generates a persistent hepatic infection, as occurs in the remainder. Once chronic infection is established, the velocity of hepatocyte injury and resultant fibrosis is significantly modulated by immunologic as well as environmental factors. Immunomodulation has been the backbone of antiviral therapy despite poor understanding of its mechanism of action.
Collapse
Affiliation(s)
- David E. Kaplan
- Medicine and Research Services, Philadelphia VA Medical Center, Philadelphia PA,Division of Gastroenterology, Department of Medicine, University of Pennsylvania
| |
Collapse
|
|
23
|
Abstract
Chronic viral infections represent a unique challenge to the infected host. Persistently replicating viruses outcompete or subvert the initial antiviral response, allowing the establishment of chronic infections that result in continuous stimulation of both the innate and adaptive immune compartments. This causes a profound reprogramming of the host immune system, including attenuation and persistent low levels of type I interferons, progressive loss (or exhaustion) of CD8(+) T cell functions, and specialization of CD4(+) T cells to produce interleukin-21 and promote antibody-mediated immunity and immune regulation. Epigenetic, transcriptional, posttranscriptional, and metabolic changes underlie this adaptation or recalibration of immune cells to the emerging new environment in order to strike an often imperfect balance between the host and the infectious pathogen. In this review we discuss the common immunological hallmarks observed across a range of different persistently replicating viruses and host species, the underlying molecular mechanisms, and the biological and clinical implications.
Collapse
Affiliation(s)
- Elina I Zuniga
- Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093;
| | - Monica Macal
- Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093;
| | - Gavin M Lewis
- Molecular Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093;
| | - James A Harker
- Section of Inflammation, Repair and Development, National Heart and Lung Institute, Imperial College London, London SW7 2AZ, United Kingdom
| |
Collapse
|
|
24
|
Reyes-López FE, Romeo JS, Vallejos-Vidal E, Reyes-Cerpa S, Sandino AM, Tort L, Mackenzie S, Imarai M. Differential immune gene expression profiles in susceptible and resistant full-sibling families of Atlantic salmon (Salmo salar) challenged with infectious pancreatic necrosis virus (IPNV). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2015; 53:210-221. [PMID: 26123889 DOI: 10.1016/j.dci.2015.06.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Revised: 06/15/2015] [Accepted: 06/16/2015] [Indexed: 06/04/2023]
Abstract
This study aims to identify at the expression level the immune-related genes associated with IPN-susceptible and resistant phenotypes in Atlantic salmon full-sibling families. We have analyzed thirty full-sibling families infected by immersion with IPNV and then classified as resistant or susceptible using a multivariate survival analysis based on a gamma-Cox frailty model and the Kaplan-Meier mortality curves. In four families within each group head kidneys were pooled for real-time PCR and one-color salmon-specific oligonucleotide microarray (21K) analysis at day 1 and 5 post-infection. Transcripts involved in innate response (IL-6, IFN-α), antigen presentation (HSP-70, HSP-90, MHC-I), TH1 response (IL-12, IFN-γ, CRFB6), immunosuppression (IL-10, TGF-β1) and leukocyte activation and migration (CCL-19, CD18) showed a differential expression pattern between both phenotypes, except in IL-6. In susceptible families, except for IFN-γ, the expressions dropped to basal values at day 5 post-infection. In resistant families, unlike susceptible families, levels remained high or increased (except for IL-6) at day 5. Transcriptomic analysis showed that both families have a clear differential expression pattern, resulting in a marked down-regulation in immune related genes involved in innate response, complement system, antigen recognition and activation of immune response in IPN-resistant. Down-regulation of genes, mainly related to tissue differentiation and protein degradation metabolism, was also observed in resistant families. We have identified an immune-related gene patterns associated with susceptibility and resistance to IPNV infection of Atlantic salmon. This suggests that a limited immune response is associated with resistant fish phenotype to IPNV challenge while a highly inflammatory but short response is associated with susceptibility.
Collapse
Affiliation(s)
- Felipe E Reyes-López
- Laboratorio de Inmunología, Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Alameda 3363, Correo 40, Casilla 33, Santiago, Chile; Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain.
| | - Jose S Romeo
- Departamento de Matemática y Ciencia de la Computación, Universidad de Santiago de Chile, Alameda 3363, Correo 40, Casilla 33, Santiago, Chile
| | - Eva Vallejos-Vidal
- Laboratorio de Virología, Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Alameda 3363, Correo 40, Casilla 33, Santiago, Chile; Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Sebastián Reyes-Cerpa
- Laboratorio de Inmunología, Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Alameda 3363, Correo 40, Casilla 33, Santiago, Chile
| | - Ana M Sandino
- Laboratorio de Virología, Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Alameda 3363, Correo 40, Casilla 33, Santiago, Chile
| | - Lluis Tort
- Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
| | - Simon Mackenzie
- Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain; Institute of Aquaculture, University of Stirling, FK9 4LA Stirling, UK
| | - Mónica Imarai
- Laboratorio de Inmunología, Centro de Biotecnología Acuícola, Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Alameda 3363, Correo 40, Casilla 33, Santiago, Chile.
| |
Collapse
|
|
25
|
Hetta HF, Mekky MA, Khalil NK, Mohamed WA, El-Feky MA, Ahmed SH, Daef EA, Nassar MI, Medhat A, Sherman KE, Shata MTM. Association of colonic regulatory T cells with hepatitis C virus pathogenesis and liver pathology. J Gastroenterol Hepatol 2015; 30:1543-51. [PMID: 25708446 PMCID: PMC4829205 DOI: 10.1111/jgh.12936] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/16/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Forkhead box protein P3 (FoxP3)(+) regulatory T (Treg ) cells play a fundamental role in maintaining the balance between the tissue-damaging and protective immune response to chronic hepatitis C (CHC) infection. Herein, we investigated the frequency of Treg cells in the colon and their potential relationship to the various CHC outcomes and hepatic histopathology. METHODS Colonic biopsies were collected from three groups with CHC: treatment naïve (TN; n = 20), non-responders (NR; n = 20), sustained virologic response (SVR; n = 20), and a fourth healthy control group (n = 10). The plasma viral loads and cytokines levels were determined by quantitative real-time polymerase chain reaction, and ELISA, respectively. Liver biopsies were examined to assess inflammatory score and fibrosis stage. Colonic Treg frequency was estimated by immunohistochemistry using confocal microscopy. RESULTS A significant increase in the frequency of colonic Treg was found in TN, and NR groups compared with the control and SVR group. The frequency of colonic Treg , plasma interleukin (IL)-10 and IL-4 levels were significantly positively correlated with viral load and negatively correlated with METAVIR inflammatory score, and fibrosis stages. CONCLUSION Colonic Treg cells are negatively correlated with liver inflammation and hepatitis C virus (HCV) viral load, which suggests a strong linkage between gut-derived Treg cell populations and HCV infection.
Collapse
Affiliation(s)
- Helal F Hetta
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio, USA,Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A Mekky
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Nasr K Khalil
- Assiut Liver Institute for Treatment of Hepatitis C, Assiut, Egypt
| | - Wegdan A Mohamed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Feky
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Shabaan H Ahmed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Enas A Daef
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud I Nassar
- Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ahmed Medhat
- Department of Gastroenterology and Tropical Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Kenneth E Sherman
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio, USA
| | - Mohamed Tarek M Shata
- Department of Internal Medicine, Division of Digestive Diseases, University of Cincinnati, Cincinnati, Ohio, USA
| |
Collapse
|
|
26
|
Kaźmierczak J, Caraballo Cortes K, Bukowska-Ośko I, Radkowski M. Virus-Specific Cellular Response in Hepatitis C Virus Infection. Arch Immunol Ther Exp (Warsz) 2015; 64:101-10. [PMID: 26429740 DOI: 10.1007/s00005-015-0364-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Accepted: 06/08/2015] [Indexed: 12/15/2022]
Abstract
Studies performed on chimpanzees and humans have revealed that strong, multispecific and sustained CD4(+) and CD8(+) T cell immune responses is a major determinant of hepatitis C virus (HCV) clearance. However, spontaneous elimination of the virus occurs in minority of infected individuals and cellular response directed against HCV antigens is not persistent in individuals with chronic infection. This review presents characteristics of the HCV-specific T cell response in patients with different clinical course of infection, including acute and chronic infection, persons who spontaneously eliminated HCV and non-infected subjects exposed to HCV. Detection of HCV-specific response, especially in non-infected subjects exposed to HCV, may be indicative of HCV prevalence in population and rate of spontaneous viral clearance. Understanding the mechanisms and role of HCV-specific cellular immune response would contribute to better understanding of HCV epidemiology, immunopathogenesis and may help to design an effective vaccine.
Collapse
Affiliation(s)
- Justyna Kaźmierczak
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland.
| | - Kamila Caraballo Cortes
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland
| | - Iwona Bukowska-Ośko
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland
| | - Marek Radkowski
- Department of Immunopathology of Infectious and Parasitic Diseases, Medical University of Warsaw, Pawińskiego 3c, 02-106, Warsaw, Poland
| |
Collapse
|
|
27
|
Cytokine Profiles and Cell Proliferation Responses to Truncated ORF2 Protein in Iranian Patients Recovered from Hepatitis E Infection. J Trop Med 2015; 2015:523560. [PMID: 26451149 PMCID: PMC4586975 DOI: 10.1155/2015/523560] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 08/23/2015] [Accepted: 09/02/2015] [Indexed: 12/16/2022] Open
Abstract
Background. The aim of this study was to evaluate hepatitis E virus (HEV) specific cellular immune responses to truncated ORF2 protein in Iranian patients recovered from HEV infection. Information about HEV-specific immune responses could be useful in finding an effective way for development of HEV vaccine. Methods. A truncated form of HEV ORF2 protein containing amino acids 112-608 was used to stimulate peripheral blood mononuclear cells (PBMCs) separated from HEV-recovered and control groups. Finally, the levels of four cytokines, IFN-γ ELISPOT, and cell proliferative responses following stimulation with the truncated ORF2 protein were assessed in the both groups. Results. The truncated ORF2 protein was able to induce IFN-γ ELISPOT and cell proliferation responses and to produce significant amounts of IFN-γ and IL-12 cytokines, but low amounts of IL-10 and IL-4 cytokines in vitro. These responses were significantly higher in the recovered group compared to the control group. These results indicate the antigenic nature of the truncated ORF2 protein and production of T helper type 1 cytokines. Conclusion. The truncated ORF2 protein can effectively induce significant cellular immune responsesand can be introduced as a potential vaccine candidate. However, further studies are required to evaluate this protein in vivo.
Collapse
|
|
28
|
Richert-Spuhler LE, Lund JM. The Immune Fulcrum: Regulatory T Cells Tip the Balance Between Pro- and Anti-inflammatory Outcomes upon Infection. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2015; 136:217-43. [PMID: 26615099 DOI: 10.1016/bs.pmbts.2015.07.015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Regulatory T cells (Tregs) are indispensable for immune homeostasis and the prevention of autoimmunity. In the context of infectious diseases, Tregs are multidimensional. Here, we describe how they may potentiate effector responses by assisting in recruitment of T cells into the infection site to resolve infection, facilitate accelerated antigen-specific memory responses, limit pathology, and contribute to disease resolution and healing, to the great benefit of the host. We also explore the villainous functions of Tregs during infection by reviewing several diseases in which the depletion or reduction in Treg frequency allows for better generation of effector memory, and results in acute resolution of infection, as opposed to chronicity or severe long-term outcomes. We describe findings generated using mouse models of infection as well as experiments performed using human cells and tissues. We propose that Tregs represent an immunologic fulcrum, promoting both pathogen clearance and damage control by preventing excessive destruction of infected tissues though unchecked immune responses.
Collapse
Affiliation(s)
- Laura E Richert-Spuhler
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Jennifer M Lund
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Department of Global Health, University of Washington, Seattle, Washington, USA.
| |
Collapse
|
|
29
|
Immunization with Recombinant Adenoviral Vectors Expressing HCV Core or F Proteins Leads to T Cells with Reduced Effector Molecules Granzyme B and IFN-γ: A Potential New Strategy for Immune Evasion in HCV Infection. Viral Immunol 2015; 28:309-24. [DOI: 10.1089/vim.2015.0009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
|
|
30
|
Regulatory T Cells in Autoimmune and Viral Chronic Hepatitis. J Immunol Res 2015; 2015:479703. [PMID: 26106627 PMCID: PMC4464004 DOI: 10.1155/2015/479703] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2015] [Accepted: 05/21/2015] [Indexed: 12/26/2022] Open
Abstract
In both autoimmune liver disease and chronic viral hepatitis, the injury results from an immune-mediated cytotoxic T cell response to liver cells. As such, it is not surprising that CD4(+) regulatory T cells, a key regulatory population of T cells able to curb immune responses, could be involved in both autoimmune hepatitis and chronic viral hepatitis. The liver can induce the conversion of naïve CD4(+) T cells to CD4(+) regulatory T cells and induce tolerance to locally expressed antigens. This tolerance mechanism is carefully regulated in physiological conditions but any imbalance could be pathological. An overly tolerant immune response can lead to chronic infections while an overreactive and unbridled immune response can lead to autoimmune hepatitis. With the recent advent of monoclonal antibodies able to target regulatory T cells (daclizumab) and improve immune responses and several ongoing clinical trials analysing the impact of regulatory T cell infusion on autoimmune liver disease or liver transplant tolerance, modulation of immunological tolerance through CD4(+) regulatory T cells could be a key element of future immunotherapies for several liver diseases allowing restoring the balance between proper immune responses and tolerance. .
Collapse
|
|
31
|
Taherkhani R, Farshadpour F, Makvandi M. Design and production of a multiepitope construct derived from hepatitis E virus capsid protein. J Med Virol 2015; 87:1225-34. [PMID: 25784455 PMCID: PMC7159329 DOI: 10.1002/jmv.24171] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2015] [Indexed: 11/15/2022]
Abstract
The aim of this study was to design a high density multiepitope protein, which can be a promising multiepitope vaccine candidate against Hepatitis E virus (HEV). Initially, conserved and antigenic helper T‐lymphocyte (HTL) epitopes in the HEV capsid protein were predicted by in silico analysis. Subsequently, a multiepitope comprising four HTL epitopes with high‐affinity binding to the HLA molecules was designed, and repeated four times as high density multiepitope construct. This construct was synthesized and cloned into pET‐30a (+) vector. Then, it was transformed and expressed in Escherichia coli BL21 cells. The high density multiepitope protein was purified by Ni‐NTA agarose and concentrated using Amicon filters. Finally, the immunological properties of this high density multiepitope protein were evaluated in vitro. The results showed that the high density multiepitope construct was successfully expressed and purified. SDS‐PAGE and Western blot analyses showed the presence of a high density multiepitope protein band of approximately 33 kDa. Approximately 1 mg of the purified protein was obtained from each liter of the culture media. Moreover, the purified multiepitope protein was capable of induction of proliferation responses, IFN‐γ ELISPOT responses and IFN‐γ and IL‐12 cytokines production in a significant level in peripheral blood mononuclear cells (PBMCs) isolated from HEV‐recovered individuals compared to the control group. In conclusion, the newly produced multiepitope protein can induce significant T helper type 1 responses in vitro, and can be considered as a novel strategy for the development of HEV vaccines in the future. J. Med. Virol. 87:1225–1234, 2015. © 2015 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Reza Taherkhani
- Department of Microbiology and Parasitology, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran; Persian Gulf Biomedical Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
| | | | | |
Collapse
|
|
32
|
Jiang ZH, Khoso PA, Yao HD, Zhang ZW, Zhang XY, Xu SW. SelW regulates inflammation-related cytokines in response to H2O2in Se-deficient chicken liver. RSC Adv 2015. [DOI: 10.1039/c4ra16055j] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Selenium (Se) deficiency-induced liver damage is related to oxidative stress, and the alternative transcription of cytokines has been linked to liver disease.
Collapse
Affiliation(s)
- Zhi-Hui Jiang
- College of Veterinary Medicine
- Northeast Agricultural University
- Harbin
- P. R. China
- College of Veterinary Medicine
| | - Pervez Ahmed Khoso
- College of Veterinary Medicine
- Northeast Agricultural University
- Harbin
- P. R. China
| | - Hai-Dong Yao
- College of Veterinary Medicine
- Northeast Agricultural University
- Harbin
- P. R. China
| | - Zi-Wei Zhang
- College of Veterinary Medicine
- Northeast Agricultural University
- Harbin
- P. R. China
| | - Xiao-Ying Zhang
- College of Veterinary Medicine
- Northwest A&F University
- Yangling
- P. R. China
| | - Shi-wen Xu
- College of Veterinary Medicine
- Northeast Agricultural University
- Harbin
- P. R. China
| |
Collapse
|
|
33
|
Reyes-Cerpa S, Reyes-López F, Toro-Ascuy D, Montero R, Maisey K, Acuña-Castillo C, Sunyer JO, Parra D, Sandino AM, Imarai M. Induction of anti-inflammatory cytokine expression by IPNV in persistent infection. FISH & SHELLFISH IMMUNOLOGY 2014; 41:172-182. [PMID: 25193394 DOI: 10.1016/j.fsi.2014.08.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Revised: 08/18/2014] [Accepted: 08/25/2014] [Indexed: 06/03/2023]
Abstract
Infectious Pancreatic Necrosis Virus (IPNV) is the agent of a well-characterized acute disease that produces a systemic infection and high mortality in farmed fish species but also persistent infection in surviving fish after outbreaks. Because viral persistence of susceptible mammal hosts appears to be associated with the modulation of anti-inflammatory cytokine expression, in this study we examined the expression levels of key pro- and anti-inflammatory cytokines in kidney and spleen of trout, as well as humoral immune response (IgM and IgT) during experimental persistent viral infection and in the acute phase of infection as a comparison. IPNV infection in rainbow trout resulted in a distinct profile of cytokine expression depending on the type of infection, acute or persistent. Levels of early pro-inflammatory cytokines, IL-1β and IL-8, did not increase in the head kidney of the fish with persistent asymptomatic infection but increased in some of the symptomatic infected fish. The antiviral cytokine IFNα was not significantly induced in any of the infected fish groups. The level of expression of the Th1-related cytokine IL-12 was significantly higher in trout with persistent asymptomatic infection than in symptomatic fish. This was also accompanied by an increase in IFNγ. The anti-inflammatory cytokines IL-10 and TGF-β1 had distinct expression profiles. While IL-10 expression increased in all infected fish, TGF-β1 was only up-regulated in fish with persistent infection. All infected fish had significantly lower total IgM levels than the non-infected fish whereas IgT levels did not change. Specific and neutralizing antibodies against IPNV were not observed in acute and persistent infection except in the group of fish with the lowest degree of clinical signs. Interestingly, the lack of humoral immune response could be associated with the high expression of anti-inflammatory cytokines, which might inhibit antibody production. The balance between pro-inflammatory Th1 type cytokines and the regulatory cytokines could explain the high percentage of survival and the resolution of the inflammatory response in the IPNV-infected fish but also the establishment of viral persistence.
Collapse
Affiliation(s)
- Sebastián Reyes-Cerpa
- Laboratorio de Inmunología, Centro de Biotecnología Acuícola (CBA), Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile.
| | - Felipe Reyes-López
- Laboratorio de Inmunología, Centro de Biotecnología Acuícola (CBA), Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Daniela Toro-Ascuy
- Laboratorio de Inmunología, Centro de Biotecnología Acuícola (CBA), Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Ruth Montero
- Laboratorio de Inmunología, Centro de Biotecnología Acuícola (CBA), Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Kevin Maisey
- Laboratorio de Inmunología, Centro de Biotecnología Acuícola (CBA), Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Claudio Acuña-Castillo
- Laboratorio de Inmunoterapia, Centro de Biotecnología Acuícola (CBA), Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - J Oriol Sunyer
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - David Parra
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Ana María Sandino
- Laboratorio de Virología, Centro de Biotecnología Acuícola (CBA), Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile
| | - Mónica Imarai
- Laboratorio de Inmunología, Centro de Biotecnología Acuícola (CBA), Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile.
| |
Collapse
|
|
34
|
Control of the inflammatory response mechanisms mediated by natural and induced regulatory T-cells in HCV-, HTLV-1-, and EBV-associated cancers. Mediators Inflamm 2014; 2014:564296. [PMID: 25525301 PMCID: PMC4267219 DOI: 10.1155/2014/564296] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 06/18/2014] [Accepted: 07/30/2014] [Indexed: 02/07/2023] Open
Abstract
Virus infections are involved in chronic inflammation and, in some cases, cancer development. Although a viral infection activates the immune system's response that eradicates the pathogen mainly through inflammatory mechanisms, it is now recognized that this inflammatory condition is also favorable to the development of tumors. Indeed, it is well described that viruses, such as hepatitis C virus (HCV), Epstein Barr virus (EBV), human papillomavirus (HPV) or human T-cell lymphotropic virus type-1 (HTLV-1), are important risk factors for tumor malignancies. The inflammatory response is a fundamental immune mechanism which involves several molecular and cellular components consisting of cytokines and chemokines that are released by various proinflammatory cells. In parallel to this process, some endogenous recruited components release anti-inflammatory mediators to restore homeostasis. The development of tools and strategies using viruses to hijack the immune response is mostly linked to the presence of regulatory T-cells (Treg) that can inhibit inflammation and antiviral responses of other effector cells. In this review, we will focus on current understanding of the role of natural and induced Treg in the control and the resolution of inflammatory response in HCV-, HTLV-1-, and EBV-associated cancers.
Collapse
|
|
35
|
Prajeeth CK, Beineke A, Iskandar CD, Gudi V, Herder V, Gerhauser I, Haist V, Teich R, Huehn J, Baumgärtner W, Stangel M. Limited role of regulatory T cells during acute Theiler virus-induced encephalitis in resistant C57BL/6 mice. J Neuroinflammation 2014; 11:180. [PMID: 25391297 PMCID: PMC4236492 DOI: 10.1186/s12974-014-0180-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 10/08/2014] [Indexed: 01/29/2023] Open
Abstract
Background Theiler’s murine encephalomyelitis virus (TMEV) infection represents a commonly used infectious animal model to study various aspects of the pathogenesis of multiple sclerosis (MS). In susceptible SJL mice, dominant activity of Foxp3+ CD4+ regulatory T cells (Tregs) in the CNS partly contributes to viral persistence and progressive demyelination. On the other hand, resistant C57BL/6 mice rapidly clear the virus by mounting a strong antiviral immune response. However, very little is known about the role of Tregs in regulating antiviral responses during acute encephalitis in resistant mouse strains. Methods In this study, we used DEREG mice that express the diphtheria toxin (DT) receptor under control of the foxp3 locus to selectively deplete Foxp3+ Tregs by injection of DT prior to infection and studied the effect of Treg depletion on the course of acute Theiler’s murine encephalomyelitis (TME). Results As expected, DEREG mice that are on a C57BL/6 background were resistant to TMEV infection and cleared the virus within days of infection, regardless of the presence or absence of Tregs. Nevertheless, in the absence of Tregs we observed priming of stronger effector T cell responses in the periphery, which subsequently resulted in a transient increase in the frequency of IFNγ-producing T cells in the brain at an early stage of infection. Histological and flow cytometric analysis revealed that this transiently increased frequency of brain-infiltrating IFNγ-producing T cells in Treg-depleted mice neither led to an augmented antiviral response nor enhanced inflammation-mediated tissue damage. Intriguingly, Treg depletion did not change the expression of IL-10 in the infected brain, which might play a role for dampening the inflammatory damage caused by the increased number of effector T cells. Conclusion We therefore propose that unlike susceptible mice strains, interfering with the Treg compartment of resistant mice only has negligible effects on virus-induced pathologies in the CNS. Furthermore, in the absence of Tregs, local anti-inflammatory mechanisms might limit the extent of damage caused by strong anti-viral response in the CNS. Electronic supplementary material The online version of this article (doi:10.1186/s12974-014-0180-9) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Chittappen K Prajeeth
- Department of Neurology, Clinical Neuroimmunology and Neurochemistry, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
| | - Andreas Beineke
- Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, Hannover, D-30559, Germany. .,Center of Systems Neuroscience, Hannover, Germany.
| | - Cut Dahlia Iskandar
- Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, Hannover, D-30559, Germany. .,Center of Systems Neuroscience, Hannover, Germany.
| | - Viktoria Gudi
- Department of Neurology, Clinical Neuroimmunology and Neurochemistry, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany.
| | - Vanessa Herder
- Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, Hannover, D-30559, Germany.
| | - Ingo Gerhauser
- Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, Hannover, D-30559, Germany.
| | - Verena Haist
- Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, Hannover, D-30559, Germany.
| | - René Teich
- Experimental Immunology, Helmholtz Centre for Infection Research, Inhoffenstr. 7, Braunschweig, D-38124, Germany.
| | - Jochen Huehn
- Experimental Immunology, Helmholtz Centre for Infection Research, Inhoffenstr. 7, Braunschweig, D-38124, Germany.
| | - Wolfgang Baumgärtner
- Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg 17, Hannover, D-30559, Germany. .,Center of Systems Neuroscience, Hannover, Germany.
| | - Martin Stangel
- Department of Neurology, Clinical Neuroimmunology and Neurochemistry, Hannover Medical School, Carl-Neuberg-Str. 1, Hannover, 30625, Germany. .,Center of Systems Neuroscience, Hannover, Germany.
| |
Collapse
|
|
36
|
Ndure J, Flanagan KL. Targeting regulatory T cells to improve vaccine immunogenicity in early life. Front Microbiol 2014; 5:477. [PMID: 25309517 PMCID: PMC4161046 DOI: 10.3389/fmicb.2014.00477] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 08/25/2014] [Indexed: 12/26/2022] Open
Abstract
Human newborns and infants are bombarded with multiple pathogens on leaving the sterile intra-uterine environment, and yet have suboptimal innate immunity and limited immunological memory, thus leading to increased susceptibility to infections in early life. They are thus the target age group for a host of vaccines against common bacterial and viral pathogens. They are also the target group for many vaccines in development, including those against tuberculosis (TB), malaria, and HIV infection. However, neonatal and infant responses too many vaccines are suboptimal, and in the case of the polysaccharide vaccines, it has been necessary to develop the alternative conjugated formulations in order to induce immunity in early life. Immunoregulatory factors are an intrinsic component of natural immunity necessary to dampen or control immune responses, with the caveat that they may also decrease immunity to infections or lead to chronic infection. This review explores the key immunoregulatory factors at play in early life, with a particular emphasis on regulatory T cells (Tregs). It goes on to explore the role that Tregs play in limiting vaccine immunogenicity, and describes animal and human studies in which Tregs have been depleted in order to enhance vaccine responses. A deeper understanding of the role that Tregs play in limiting or controlling vaccine-induced immunity would provide strategies to improve vaccine immunogenicity in this critical age group. New adjuvants and drugs are being developed that can transiently suppress Treg function, and their use as part of human vaccination strategies against infections is becoming a real prospect for the future.
Collapse
Affiliation(s)
- Jorjoh Ndure
- Infant Immunology Group, Vaccinology Theme, Medical Research Council Laboratories Fajara, The Gambia
| | - Katie L Flanagan
- Vaccine and Infectious Diseases Laboratory, Department of Immunology, Monash University Melbourne, VIC, Australia
| |
Collapse
|
|
37
|
Ratnoglik SL, Jiang DP, Aoki C, Sudarmono P, Shoji I, Deng L, Hotta H. Induction of cell-mediated immune responses in mice by DNA vaccines that express hepatitis C virus NS3 mutants lacking serine protease and NTPase/RNA helicase activities. PLoS One 2014; 9:e98877. [PMID: 24901478 PMCID: PMC4046998 DOI: 10.1371/journal.pone.0098877] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 05/07/2014] [Indexed: 12/14/2022] Open
Abstract
Effective therapeutic vaccines against virus infection must induce sufficient levels of cell-mediated immune responses against the target viral epitopes and also must avoid concomitant risk factors, such as potential carcinogenic properties. The nonstructural protein 3 (NS3) of hepatitis C virus (HCV) carries a variety of CD4(+) and CD8(+) T cell epitopes, and induces strong HCV-specific T cell responses, which are correlated with viral clearance and resolution of acute HCV infection. On the other hand, NS3 possesses serine protease and nucleoside triphosphatase (NTPase)/RNA helicase activities, which not only play important roles in viral life cycle but also concomitantly interfere with host defense mechanisms by deregulating normal cellular functions. In this study, we constructed a series of DNA vaccines that express NS3 of HCV. To avoid the potential harm of NS3, we introduced mutations to the catalytic triad of the serine protease (H57A, D81A and S139A) and the NTPase/RNA helicase domain (K210N, F444A, R461Q and W501A) to eliminate the enzymatic activities. Immunization of BALB/c mice with each of the DNA vaccine candidates (pNS3[S139A/K210N], pNS3[S139A/F444A], pNS3[S139A/R461Q] and pNS3[S139A/W501A]) that expresses an NS3 mutant lacking both serine protease and NTPase/helicase activities induced T cell immune responses to the degree comparable to that induced by the wild type NS3 and the NS3/4A complex, as demonstrated by interferon-γ production and cytotoxic T lymphocytes activities against NS3. The present study has demonstrated that plasmids expressing NS3 mutants, NS3(S139A/K210N), NS3(S139A/F444A), NS3(S139A/R461Q) and NS3(S139A/W501A), which lack both serine protease and NTPase/RNA helicase activities, would be good candidates for safe and efficient therapeutic DNA vaccines against HCV infection.
Collapse
Affiliation(s)
- Suratno Lulut Ratnoglik
- Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan
- Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Da-Peng Jiang
- Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Chie Aoki
- Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan
- JST/JICA SATREPS Laboratory of Kobe University, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | | | - Ikuo Shoji
- Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Lin Deng
- Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hak Hotta
- Division of Microbiology, Kobe University Graduate School of Medicine, Kobe, Japan
- * E-mail:
| |
Collapse
|
|
38
|
Fernandez-Ponce C, Dominguez-Villar M, Aguado E, Garcia-Cozar F. CD4+ primary T cells expressing HCV-core protein upregulate Foxp3 and IL-10, suppressing CD4 and CD8 T cells. PLoS One 2014; 9:e85191. [PMID: 24465502 PMCID: PMC3896374 DOI: 10.1371/journal.pone.0085191] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Accepted: 11/30/2013] [Indexed: 12/11/2022] Open
Abstract
Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV-infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-γ production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127(low)PD-1(high)TIM-3(high) regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV-core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein.
Collapse
Affiliation(s)
- Cecilia Fernandez-Ponce
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
| | - Margarita Dominguez-Villar
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
| | - Enrique Aguado
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
| | - Francisco Garcia-Cozar
- Department of Biomedicine, Biotechnology and Public Health (Immunology), University of Cadiz and Puerto Real University Hospital Research Unit, School of Medicine, Cadiz, Spain
| |
Collapse
|
|
39
|
CD49b, a major marker of regulatory T-cells type 1, predicts the response to antiviral therapy of recurrent hepatitis C after liver transplantation. BIOMED RESEARCH INTERNATIONAL 2014; 2014:290878. [PMID: 24575405 PMCID: PMC3915765 DOI: 10.1155/2014/290878] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 10/08/2013] [Accepted: 10/14/2013] [Indexed: 01/22/2023]
Abstract
The TRANSPEG study was a prospective study to assess the efficacy of antiviral therapy in patients with a recurrent hepatitis C virus (HCV) after liver transplantation. The influence of regulatory T-cells (Tregs) on the response to antiviral therapy was analyzed. Patients were considered as a function of their sustained virological response (SVR) at 18 months after treatment initiation. A transcriptomic analysis was performed to assess Treg markers (Tr1 and FoxP3+) in serum, PBMC, and liver biopsies. 100 patients had been included in the TRANSPEG study. Data from 27 of these patients were available. The results showed that the expression of CD49b (a predominant marker of Tr1) before the introduction of antiviral therapy was significantly associated with SVR. Responders displayed lower serum levels of CD49b than nonresponders (P < 0.02). These findings were confirmed in PBMC and liver biopsies even if in a nonsignificant manner for the limited number of samples. The assessment of CD49b levels is thus predictive of the response to antiviral therapy. This data suggests that CD49b may be a marker of the failure of the immune response and antiviral therapy during HCV recurrence. The assessment of CD49b could help to select patients who require earlier and more intensive antiviral therapy.
Collapse
|
|
40
|
Irshad M, Mankotia DS, Irshad K. An insight into the diagnosis and pathogenesis of hepatitis C virus infection. World J Gastroenterol 2013; 19:7896-7909. [PMID: 24307784 PMCID: PMC3848138 DOI: 10.3748/wjg.v19.i44.7896] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 09/11/2013] [Accepted: 10/14/2013] [Indexed: 02/06/2023] Open
Abstract
This review focuses on research findings in the area of diagnosis and pathogenesis of hepatitis C virus (HCV) infection over the last few decades. The information based on published literature provides an update on these two aspects of HCV. HCV infection, previously called blood transmitted non-A, non-B infection, is prevalent globally and poses a serious public health problem worldwide. The diagnosis of HCV infection has evolved from serodetection of non-specific and low avidity anti-HCV antibodies to detection of viral nucleic acid in serum using the polymerase chain reaction (PCR) technique. Current PCR assays detect viral nucleic acid with high accuracy and the exact copy number of viral particles. Moreover, multiplex assays using real-time PCR are available for identification of HCV-genotypes and their isotypes. In contrast to previous methods, the newly developed assays are not only fast and economic, but also resolve the problem of the window period as well as differentiate present from past infection. HCV is a non-cytopathic virus, thus, its pathogenesis is regulated by host immunity and metabolic changes including oxidative stress, insulin resistance and hepatic steatosis. Both innate and adaptive immunity play an important role in HCV pathogenesis. Cytotoxic lymphocytes demonstrate crucial activity during viral eradication or viral persistence and are influenced by viral proteins, HCV-quasispecies and several metabolic factors regulating liver metabolism. HCV pathogenesis is a very complex phenomenon and requires further study to determine the other factors involved.
Collapse
|
|
41
|
Mueller C, Chulay JD, Trapnell BC, Humphries M, Carey B, Sandhaus RA, McElvaney NG, Messina L, Tang Q, Rouhani FN, Campbell-Thompson M, Fu AD, Yachnis A, Knop DR, Ye GJ, Brantly M, Calcedo R, Somanathan S, Richman LP, Vonderheide RH, Hulme MA, Brusko TM, Wilson JM, Flotte TR. Human Treg responses allow sustained recombinant adeno-associated virus-mediated transgene expression. J Clin Invest 2013; 123:5310-8. [PMID: 24231351 DOI: 10.1172/jci70314] [Citation(s) in RCA: 119] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Accepted: 09/12/2013] [Indexed: 02/04/2023] Open
Abstract
Recombinant adeno-associated virus (rAAV) vectors have shown promise for the treatment of several diseases; however, immune-mediated elimination of transduced cells has been suggested to limit and account for a loss of efficacy. To determine whether rAAV vector expression can persist long term, we administered rAAV vectors expressing normal, M-type α-1 antitrypsin (M-AAT) to AAT-deficient subjects at various doses by multiple i.m. injections. M-specific AAT expression was observed in all subjects in a dose-dependent manner and was sustained for more than 1 year in the absence of immune suppression. Muscle biopsies at 1 year had sustained AAT expression and a reduction of inflammatory cells compared with 3 month biopsies. Deep sequencing of the TCR Vβ region from muscle biopsies demonstrated a limited number of T cell clones that emerged at 3 months after vector administration and persisted for 1 year. In situ immunophenotyping revealed a substantial Treg population in muscle biopsy samples containing AAT-expressing myofibers. Approximately 10% of all T cells in muscle were natural Tregs, which were activated in response to AAV capsid. These results suggest that i.m. delivery of rAAV type 1-AAT (rAAV1-AAT) induces a T regulatory response that allows ongoing transgene expression and indicates that immunomodulatory treatments may not be necessary for rAAV-mediated gene therapy.
Collapse
MESH Headings
- Biopsy
- Capsid/immunology
- Clone Cells/chemistry
- Dependovirus/genetics
- Dependovirus/immunology
- Gene Expression Regulation/immunology
- Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
- Genetic Therapy
- Genetic Vectors/immunology
- Genetic Vectors/therapeutic use
- Humans
- Injections, Intramuscular
- Lymphocyte Activation
- Muscle, Skeletal/chemistry
- Muscle, Skeletal/immunology
- Muscle, Skeletal/pathology
- Muscle, Skeletal/virology
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Recombinant Fusion Proteins/biosynthesis
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/immunology
- T-Lymphocytes, Regulatory/immunology
- Transgenes/immunology
- alpha 1-Antitrypsin/biosynthesis
- alpha 1-Antitrypsin/genetics
- alpha 1-Antitrypsin/immunology
- alpha 1-Antitrypsin Deficiency/therapy
Collapse
|
|
42
|
Wang F, Yao K, Yin QZ, Zhou F, Ding CL, Peng GY, Xu J, Chen Y, Feng DJ, Ma CL, Xu WR. Human Herpesvirus-6-Specific Interleukin 10-Producing CD4+T Cells Suppress the CD4+T-Cell Response in Infected Individuals. Microbiol Immunol 2013; 50:787-803. [PMID: 17053315 DOI: 10.1111/j.1348-0421.2006.tb03855.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Human herpesvirus-6 (HHV-6) infection normally persists for the lifetime of the host and may reactivate with immunosuppression. The mechanism behind HHV-6 latent infection is still not fully understood. In this study, we observed that decreased proliferation of CD4+ T cells and PBMCs but not CD8+ T cells from HHV-6-infected individuals was stimulated with HHV-6-infected cell lysates. Moreover, HHV-6-stimulated CD4+ T cells from HHV-6-infected individuals have suppressive activity on naïve CD4+ T and CD8+ T cells from HHV-6-uninfected individuals. However, no increased proportion of CD4+ CD25+ Treg cells from HHV-6-infected individuals contributed to the suppressive activity of the HHV-6-stimulated CD4+ T cells from HHV-6-infected individuals. Transwell experiments, ELISA and anti-IL-10 antibody blocking experiment demonstrated that IL-10 may be the suppressive cytokine required for suppressive activity of CD4+ T cells from HHV-6-infected individuals. Results of intracellular interleukin (IL)-10 and IL-4 further implicated the HHV-6-specific IL-10-producing CD4+ T cells in the suppressive activity of CD4+ T cells from HHV-6-infected individuals. Results of intracellular interferon (IFN)-gamma demonstrated a decreased frequency of HHV-6-specific IFN-gamma-producing CD4+ T, but not CD8+ T cells in HHV-6-infected individuals, indicating that it was the CD4+ Th1 responses in HHV-6-infected individuals that were selectively impaired. Our findings indicated that HHV-6-specific IL-10-producing CD4+ T cells from HHV-6-infected individuals possess T regulatory type 1 cell activity: immunosuppression, high levels of IL-10 production, with a few cells expressing IFN-gamma, but none expressing IL-4. These cells may play an important role in latent HHV-6 infection.
Collapse
Affiliation(s)
- Fang Wang
- Department of Microbiology and Immunology, NanJing Medical University, 140 Han Zhong Road, Nanjing 210029, Jiangsu, P.R. China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Overexpression of Regulatory T Cells Type 1 (Tr1) Specific Markers in a Patient with HCV-Induced Hepatocellular Carcinoma. ISRN HEPATOLOGY 2013; 2013:928485. [PMID: 27335834 PMCID: PMC4890904 DOI: 10.1155/2013/928485] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 07/24/2013] [Indexed: 01/14/2023]
Abstract
Hepatitis C virus (HCV) is an important causative agent of liver disease, but factors that determine the resolution or progression of infection are poorly understood. In this study, we suggested that existence of immunosuppressive mechanisms, supported by regulatory T cells and especially the regulatory T cell 1 subset (Tr1), may explain the impaired immune response during infection and thus the fibrosis aggravation to hepatocellular carcinoma (HCC). Using quantitative real-time PCR, we investigated the intra-hepatic presence of Tr1 cells in biopsies from a genotype 1b infected patient followed for an 18-year period from cirrhosis to HCC. We described a significant increase of gene expression in particular for the cytokines IL-10, TGF-β, and their receptors that were perfectly correlated with an increased expression of the Tr1 specific markers (combined expression of CD4, CD18, and CD49b). This was strongly marked since the patient evolved in the pathology and could explain the failure of the treatment. In conclusion, evidence of regulatory T cell installation in the liver of chronically infected patient with cirrhosis and HCC suggests for the first time a key role for these cells in the course of HCV infection.
Collapse
|
|
44
|
Dynamic changes of Foxp3(+) regulatory T cells in spleen and brain of canine distemper virus-infected dogs. Vet Immunol Immunopathol 2013; 156:215-22. [PMID: 24210687 DOI: 10.1016/j.vetimm.2013.10.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Revised: 09/25/2013] [Accepted: 10/08/2013] [Indexed: 01/08/2023]
Abstract
Canine distemper virus (CDV) infection causes immunosuppression and demyelinating leukoencephalitis in dogs. In viral diseases, an ambiguous function of regulatory T cells (Treg), with both beneficial effects by reducing immunopathology and detrimental effects by inhibiting antiviral immunity, has been described. However, the role of Treg in the pathogenesis of canine distemper remains unknown. In order to determine the effect of CDV upon immune homeostasis, the amount of Foxp3(+) Treg in spleen and brain of naturally infected dogs has been determined by immunohistochemistry. In addition, splenic cytokine expression has been quantified by reverse transcriptase polymerase chain reaction. Splenic depletion of Foxp3(+) Treg was associated with an increased mRNA-expression of tumor necrosis factor and decreased transcription of interleukin-2 in the acute disease phase, indicative of disturbed immunological counter regulation in peripheral lymphoid organs. In the brain, a lack of Foxp3(+) Treg in predemyelinating and early demyelinating lesions and significantly increased infiltrations of Foxp3(+) Treg in chronic demyelinating lesions were observed. In conclusion, disturbed peripheral and CNS immune regulation associated with a reduction of Treg represents a potential prerequisite for excessive neuroinflammation and early lesion development in canine distemper leukoencephalitis.
Collapse
|
|
45
|
Cusick MF, Libbey JE, Cox Gill J, Fujinami RS, Eckels DD. CD4 + T-cell engagement by both wild-type and variant HCV peptides modulates the conversion of viral clearing helper T cells to Tregs. Future Virol 2013; 8. [PMID: 24421862 DOI: 10.2217/fvl.13.49] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
AIM To determine whether modulation of T-cell responses by naturally occurring viral variants caused an increase in numbers of Tregs in HCV-infected patients. PATIENTS MATERIALS & METHODS Human peripheral blood mononuclear cells, having proliferative responses to a wild-type HCV-specific CD4+ T-cell epitope, were used to quantify, via proliferative assays, flow cytometry and class II tetramers, the effects of naturally occurring viral variants arising in the immunodominant epitope. RESULTS In combination, the wild-type and variant peptides led to enhanced suppression of an anti-HCV T-cell response. The variant had a lower avidity for the wild-type-specific CD4+ T cell. Variant-stimulated CD4+ T cells had increased Foxp3, compared with wild-type-stimulated cells. CONCLUSION A stable viral variant from a chronic HCV subject was able to induce Tregs in multiple individuals that responded to the wild-type HCV-specific CD4+ T-cell epitope.
Collapse
Affiliation(s)
- Matthew F Cusick
- Department of Pathology, University of Utah School of Medicine, 30 North 1900 East, 3R330 SOM, Salt Lake City, UT 84132, USA
| | - Jane E Libbey
- Department of Pathology, University of Utah School of Medicine, 30 North 1900 East, 3R330 SOM, Salt Lake City, UT 84132, USA
| | - Joan Cox Gill
- Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI 53226, USA
| | - Robert S Fujinami
- Department of Pathology, University of Utah School of Medicine, 30 North 1900 East, 3R330 SOM, Salt Lake City, UT 84132, USA
| | - David D Eckels
- Department of Pathology, University of Utah School of Medicine, 30 North 1900 East, 3R330 SOM, Salt Lake City, UT 84132, USA
| |
Collapse
|
|
46
|
Self AA, Losikoff PT, Gregory SH. Divergent contributions of regulatory T cells to the pathogenesis of chronic hepatitis C. Hum Vaccin Immunother 2013; 9:1569-76. [PMID: 23732899 DOI: 10.4161/hv.24726] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Hepatitis C virus, a small single-stranded RNA virus, is a major cause of chronic liver disease. Resolution of primary hepatitis C virus infections depends upon the vigorous responses of CD4(+) and CD8(+) T cells to multiple viral epitopes. Although such broad CD4(+) and CD8(+) T-cell responses are readily detected early during the course of infection regardless of clinical outcome, they are not maintained in individuals who develop chronic disease. Purportedly, a variety of factors contribute to the diminished T-cell responses observed in chronic, virus-infected patients including the induction of and biological suppression by CD4(+)FoxP3(+) regulatory T cells. Indeed, a wealth of evidence suggests that regulatory T cells play diverse roles in the pathogenesis of chronic hepatitis C, impairing the effector T-cell response and viral clearance early during the course of infection and suppressing liver injury as the disease progresses. The factors that affect the generation and biological response of regulatory T cells in chronic, hepatitis C virus-infected patients is discussed.
Collapse
Affiliation(s)
- Ayssa A Self
- Department of Medicine; Rhode Island Hospital and the Warren Alpert Medical School of Brown University; Providence, RI USA
| | | | | |
Collapse
|
|
47
|
Yue M, Deng X, Zhai X, Xu K, Kong J, Zhang J, Zhou Z, Yu X, Xu X, Liu Y, Zhu D, Zhang Y. Th1 and Th2 cytokine profiles induced by hepatitis C virus F protein in peripheral blood mononuclear cells from chronic hepatitis C patients. Immunol Lett 2013; 152:89-95. [PMID: 23680070 DOI: 10.1016/j.imlet.2013.05.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Revised: 05/04/2013] [Accepted: 05/05/2013] [Indexed: 12/28/2022]
Abstract
Th1 and Th2 cytokine response has been confirmed to be correlated with the pathogenesis of HCV infection. The aim of the study is to investigate the Th1 and Th2 cytokine profiles induced by HCV alternate reading frame protein (F protein) in chronic hepatitis C patients. We assessed the immune responses specific to HCV F protein in 55 chronic HCV patients. IFN-γ, IL-2, IL-4 and IL-5 secretion by peripheral blood mononuclear cells (PBMC) post F protein stimulation were compared among HCV patients and healthy donors. Finally, the associations between HCV F protein and HLA class II alleles were explored. We found that the seroprevalence of anti-F antibodies in HCV-related hepatocellular carcinoma (HCC) patients was significantly higher than that of patients without HCC, but such a significant difference in humoral immune responses to F protein was not observed in HCV 1b-infected- and non-HCV 1b-infected-patients. Additionally, the PBMC proliferation of HCC patients was significantly lower than that of patients without HCC. Furthermore, F protein stimulation of PBMCs from F-seropositive patients resulted in Th2 biased cytokine responses (significantly decreased IFN-γ and/or IL-2 and significantly increased IL-4 and/or IL-5 levels) that reportedly may contribute to HCC progression and pathogenesis. However, no significant difference in the association between HCV F protein and HLA-DRB1*0201, 0301, 0405, 1001 and HLA-DQB1*0201, 0401, 0502, 0602 was observed in this study. These findings suggest that F protein may contribute to the HCV-associated bias in Th1/Th2 responses of chronic hepatitis C patients including the progress of HCC pathogenesis.
Collapse
Affiliation(s)
- Ming Yue
- School of Life Science and Technology, China Pharmaceutical University, No. 24 Tongjiaxiang, Nanjing, Jiangsu Province, China
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Myers L, Joedicke JJ, Carmody AB, Messer RJ, Kassiotis G, Dudley JP, Dittmer U, Hasenkrug KJ. IL-2-independent and TNF-α-dependent expansion of Vβ5+ natural regulatory T cells during retrovirus infection. THE JOURNAL OF IMMUNOLOGY 2013; 190:5485-95. [PMID: 23645880 DOI: 10.4049/jimmunol.1202951] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Friend virus infection of mice induces the expansion and activation of regulatory T cells (Tregs) that dampen acute immune responses and promote the establishment and maintenance of chronic infection. Adoptive transfer experiments and the expression of neuropilin-1 indicate that these cells are predominantly natural Tregs rather than virus-specific conventional CD4(+) T cells that converted into induced Tregs. Analysis of Treg TCR Vβ chain usage revealed a broadly distributed polyclonal response with a high proportionate expansion of the Vβ5(+) Treg subset, which is known to be responsive to endogenous retrovirus-encoded superantigens. In contrast to the major population of Tregs, the Vβ5(+) subset expressed markers of terminally differentiated effector cells, and their expansion was associated with the level of the antiviral CD8(+) T cell response rather than the level of Friend virus infection. Surprisingly, the expansion and accumulation of the Vβ5(+) Tregs was IL-2 independent but dependent on TNF-α. These experiments reveal a subset-specific Treg induction by a new pathway.
Collapse
Affiliation(s)
- Lara Myers
- Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA
| | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Predicted peptides from non-structural proteins of porcine reproductive and respiratory syndrome virus are able to induce IFN-γ and IL-10. Viruses 2013; 5:663-77. [PMID: 23435238 PMCID: PMC3640520 DOI: 10.3390/v5020663] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2012] [Revised: 02/07/2013] [Accepted: 02/09/2013] [Indexed: 01/09/2023] Open
Abstract
This work describes peptides from non-structural proteins (nsp) of porcine reproductive and respiratory syndrome virus (PRRSV) predicted as potential T cell epitopes by bioinfornatics and tested for their ability to induce IFN-γ and IL-10 responses. Pigs immunized with either genotype 1 or genotype 2 PRRSV attenuated vaccines (n=5/group) and unvaccinated pigs (n = 4) were used to test the peptides. Swine leukocyte antigen haplotype of each pig was also determined. Pigs were initially screened for IFN-γ responses (ELISPOT) and three peptides were identified; two of them in non-conserved segments of nsp2 and nsp5 and the other in a conserved region of nsp5 peptide. Then, peptides were screened for IL-10 inducing properties. Six peptides were found to induce IL-10 release in PBMC and some of them were also able to inhibit IFN-γ responses on PHA-stimulated cells. Interestingly, the IFN-γ low responder pigs against PRRSV were mostly homozygous for their SLA haplotypes. In conclusion, these results indicate that nsp of PRRSV contain T-cell epitopes inducing IFN-γ responses as well as IL-10 inducing segments with inhibitory capabilities.
Collapse
|
|
50
|
Myeloid-derived suppressor cells in murine retrovirus-induced AIDS inhibit T- and B-cell responses in vitro that are used to define the immunodeficiency. J Virol 2012; 87:2058-71. [PMID: 23221564 DOI: 10.1128/jvi.01547-12] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) have been characterized in several disease settings, especially in many tumor systems. Compared to their involvement in tumor microenvironments, however, MDSCs have been less well studied in their responses to infectious disease processes, in particular to retroviruses that induce immunodeficiency. Here, we demonstrate for the first time the development of a highly immunosuppressive MDSC population that is dependent on infection by the LP-BM5 retrovirus, which causes murine acquired immunodeficiency. These MDSCs express a cell surface marker signature (CD11b(+) Gr-1(+) Ly6C(+)) characteristic of monocyte-type MDSCs. Such MDSCs profoundly inhibit immune responsiveness by a cell dose- and substantially inducible nitric oxide synthase (iNOS)-dependent mechanism that is independent of arginase activity, PD-1-PD-L1 expression, and interleukin 10 (IL-10) production. These MDSCs display levels of immunosuppressive function in parallel with the extent of disease in LP-BM5-infected wild-type (w.t.) versus knockout mouse strains that are differentially susceptible to pathogenesis. These MDSCs suppressed not only T-cell but also B-cell responses, which are an understudied target for MDSC inhibition. The MDSC immunosuppression of B-cell responses was confirmed by the use of purified B responder cells, multiple B-cell stimuli, and independent assays measuring B-cell expansion. Retroviral load measurements indicated that the suppressive Ly6G(low/±) Ly6C(+) CD11b(+)-enriched MDSC subset was positive for LP-BM5, albeit at a significantly lower level than that of nonfractionated splenocytes from LP-BM5-infected mice. These results, including the strong direct MDSC inhibition of B-cell responsiveness, are novel for murine retrovirus-induced immunosuppression and, as this broadly suppressive function mirrors that of the LP-BM5-induced disease syndrome, support a possible pathogenic effector role for these retrovirus-induced MDSCs.
Collapse
|