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Li N, Tong C, Chen Y, Yang Z, Zhou Y. Increased Peripheral Interleukin-35 Suppresses CD4 + T and CD8 + T-Cell Activity in Patients Living with Chronic Human Immunodeficiency Virus-1 Infection. Viral Immunol 2025; 38:96-106. [PMID: 40131183 DOI: 10.1089/vim.2024.0085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2025] Open
Abstract
Interleukin-35 (IL-35) has an immunosuppressive function through the regulation of immune cells during infectious diseases, autoimmune disorders, and cancers. The modulatory role of IL-35 in T lymphocytes, which are involved in host immune responses during human immunodeficiency virus-1 (HIV-1) infection, has not been elucidated. The aim of the current study was to investigate the role of regulatory function of IL-35 to T-cell activity in patients living with chronic HIV-1 infection. Sixty-seven patients living with chronic HIV-1 infection and 17 controls were enrolled in the study. IL-35 levels were measured via an enzyme-linked immunosorbent assay. Purified CD4+ and CD8+ T cells were stimulated with recombinant human IL-35. The secretion of cytokines and cytotoxic molecules, the mRNA levels of IL-35 receptor subunits and transcription factors, the expression of immune checkpoint molecules, and cell proliferation were assessed to evaluate the effect of IL-35 on T lymphocyte function in vitro. Compared with controls, patients living with chronic HIV-1 infection presented increased plasma IL-35 levels. IL-35 stimulation did not affect either the expression of IL-35 receptor subunits or the proliferation of CD4+ and CD8+ T cells from either patients living with chronic HIV-1 infection or controls. IL-35 stimulation downregulated transcription factor mRNA expression and cytokine secretion by CD4+ T cells as well as cytotoxic molecule production by CD8+ T cells from both patients living with chronic HIV-1 infection and controls. This process was accompanied by increased expression of immune checkpoint molecules on CD4+ and CD8+ T cells. The addition of IL-35 also reduced perforin and granzyme B secretion by HIV-1-specific CD8+ T cells from patients living with chronic HIV-1 infection. Increased plasma IL-35 in patients living with chronic HIV-1 infection might dampen the activation of CD4+ and CD8+ T cells, leading to T-cell exhaustion.
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Affiliation(s)
- Na Li
- Department of Clinical Laboratory, Lanzhou Pulmonary Hospital, Lanzhou, China
| | - Chongxiang Tong
- Department of Clinical Laboratory, Lanzhou Pulmonary Hospital, Lanzhou, China
| | - Yan Chen
- Department of Clinical Laboratory, Lanzhou Pulmonary Hospital, Lanzhou, China
| | - Zengwei Yang
- Department of Clinical Laboratory, Lanzhou Pulmonary Hospital, Lanzhou, China
| | - Yingquan Zhou
- Department of Infectious Diseases, Lanzhou Pulmonary Hospital, Lanzhou, China
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2
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Zhou Y, Chen J, Bai S, Yang F, Yan R, Song Y, Yang B, Li C, Wang J. Interleukin-36gamma Mediates the In Vitro Activation of CD8 + T Cells from Patients Living with Chronic Human Immunodeficiency Virus-1 Infection. Viral Immunol 2024; 37:24-35. [PMID: 38301135 DOI: 10.1089/vim.2023.0080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024] Open
Abstract
Interleukin-36 (IL-36) signaling plays an important role in promoting CD8+ T cell-mediated antitumor immune responses. The role of IL-36 signaling in CD8+ T cells that are involved in host immune responses during human immunodeficiency virus-1 (HIV-1) infection has not been characterized. Sixty-one patients living with chronic HIV-1 infection and 23 controls were enrolled in this study. The levels of IL-36 cytokine family members were measured by enzyme-linked immunosorbent assay. Purified CD8+ T cells were stimulated with recombinant IL-36gamma (1 or 10 ng/mL). The expression of inhibitory receptors, the secretion of cytotoxic molecules and interferon-gamma, and the mRNA levels of apoptosis-related ligands were assessed to evaluate the effect of IL-36gamma on CD8+ T cell function in vitro. There were no significant differences in IL-36alpha, IL-36beta, or IL-36 receptor antagonist levels between patients living with chronic HIV-1 infection and controls. Plasma IL-36gamma levels were reduced in patients living with chronic HIV-1 infection. Perforin, granzyme B, and granulysin secretion, as well as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and Fas ligand (FasL) mRNA expression, but not programmed death-1 (PD-1) or cytotoxic T lymphocyte-associated protein-4 (CTLA-4) expression was downregulated in CD8+ T cells from patients living with chronic HIV-1 infection. The addition of both 1 and 10 ng/mL IL-36gamma enhanced perforin, granzyme B, granulysin, and interferon-gamma secretion by CD8+ T cells without affecting PD-1/CTLA-4 or TRAIL/FasL mRNA expression in CD8+ T cells from patients living with chronic HIV-1 infection. The addition of 1 ng/mL IL-36gamma also promoted perforin and granzyme B secretion by HIV-1-specific CD8+ T cells from patients living with chronic HIV-1 infection. The reduced IL-36gamma levels in patients living with chronic HIV-1 infection might be insufficient for the activation of CD8+ T cells, leading to CD8+ T cell exhaustion.
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Affiliation(s)
- Yingquan Zhou
- Department of Infectious Diseases, Lanzhou Pulmonary Hospital, Lanzhou, China
| | - Jijun Chen
- Institute for STD and AIDS Prevention and Control, Lanzhou Center for Disease Control and Prevention, Lanzhou, China
| | - Shaoli Bai
- Department of Infectious Diseases, Lanzhou Pulmonary Hospital, Lanzhou, China
- Department of Internal Medicine, Gansu Province Hospital Rehabilitation Center, Lanzhou, China
| | - Fan Yang
- Department of Infectious Diseases, Lanzhou Pulmonary Hospital, Lanzhou, China
| | - Ruqing Yan
- Department of Infectious Diseases, Lanzhou Pulmonary Hospital, Lanzhou, China
| | - Yanjun Song
- Department of Infectious Diseases, Lanzhou Pulmonary Hospital, Lanzhou, China
| | - Binfa Yang
- Department of Infectious Diseases, Lanzhou Pulmonary Hospital, Lanzhou, China
| | - Chao Li
- Department of Infectious Diseases, Lanzhou Pulmonary Hospital, Lanzhou, China
| | - Jianyun Wang
- Department of Infectious Diseases, Gansu Province Hospital Rehabilitation Center, Lanzhou, China
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Allers K, Moos V, Hofmann J, Witkowski M, Haibel H, Angermair S, Schneider T. Cytolytic CD8 + T cell response to SARS-CoV-2 and non-SARS-CoV-2-related viruses is associated with severe manifestation of COVID-19. Clin Immunol 2023; 254:109712. [PMID: 37506745 DOI: 10.1016/j.clim.2023.109712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 04/26/2023] [Accepted: 07/25/2023] [Indexed: 07/30/2023]
Abstract
Little is known about the CD8+ T cell functionality in the coronavirus disease 2019 (COVID-19). Therefore, we examined twenty-five hospitalized COVID-19 patients with moderate (MD) or severe disease (SD) as well as seventeen SARS-CoV-2-unexposed persons regarding the cytolytic and cytokine-producing reactivity of their CD8+ T cells. Reactive CD8+ T cells were detectable in 90% of the unexposed persons, confirming high cross-reactive immune memory in the general population. Compared to unexposed persons and MD patients, SD patients had higher numbers of SARS-CoV-2 reactive CD8+ T cells with cytolytic function that can simultaneously produce inflammatory cytokines. In addition, SD patients showed higher CD8+ T cell reactivity against non-SARS-CoV-2-related viruses, which was mainly mediated by cytolytic response. Sequence alignments showed that cross-reactivities with the Spike protein could contribute to the expansion of such cells. Since insufficiently regulated cytolytic CD8+ T cells can damage peripheral and vascular tissue structures, high levels of both SARS-CoV-2-reactive and heterologously activated cytolytic CD8+ T cells could favor severe disease progression.
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Affiliation(s)
- Kristina Allers
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany.
| | - Verena Moos
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Jörg Hofmann
- Labor Berlin - Charité Vivantes GmbH, Sylter Straße 2, 13353 Berlin, Germany
| | - Mario Witkowski
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Microbiology, Infectious Diseases and Immunology, Laboratory of Innate Immunity, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Hildrun Haibel
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Stefan Angermair
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, Klinik für Anästhesiologie mit Schwerpunkt operative Intensivmedizin, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany
| | - Thomas Schneider
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Division of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany
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Latif MB, Shukla S, Del Rio Estrada PM, Ribeiro SP, Sekaly RP, Sharma AA. Immune mechanisms in cancer patients that lead to poor outcomes of SARS-CoV-2 infection. Transl Res 2022; 241:83-95. [PMID: 34871809 PMCID: PMC8641406 DOI: 10.1016/j.trsl.2021.12.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 11/28/2021] [Accepted: 12/01/2021] [Indexed: 02/09/2023]
Abstract
Patients with cancers have been severely affected by the COVID-19 pandemic. This is highlighted by the adverse outcomes in cancer patients with COVID-19 as well as by the impact of the COVID-19 pandemic on cancer care. Patients with cancer constitute a heterogeneous population that exhibits distinct mechanisms of immune dysfunction, associated with distinct systemic features of hot (T-cell-inflamed/infiltrated) and cold (Non-T-cell-inflamed and/or infiltrated) tumors. The former show hyper immune activated cells and a highly inflammatory environment while, contrastingly, the latter show the profile of a senescent and/or quiescent immune system. Thus, the evolution of SARS-CoV-2 infection in different types of cancers can show distinct trajectories which could lead to a variety of clinical and pathophysiological outcomes. The altered immunological environment including cytokines that characterizes hot and cold tumors will lead to different mechanisms of immune dysfunction, which will result in downstream effects on the course of SARS-CoV-2 infection. This review will focus on defining the known contributions of soluble pro- and anti-inflammatory mediators on immune function including altered T-cells and B-cells responses and as well on how these factors modulate the expression of SARS-CoV-2 receptor ACE2, TMPRSS2 expression, and lymph node fibrosis in cancer patients. We will propose immune mechanisms that underlie the distinct courses of SARS-CoV-2 infection in cancer patients and impact on the success of immune based therapies that have significantly improved cancer outcomes. Better understanding of the immune mechanisms prevalent in cancer patients that are associated to the outcomes of SARS-CoV-2 infection will help to identify the high-risk cancer patients and develop immune-based approaches to prevent significant adverse outcomes by targeting these pathways.
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Affiliation(s)
- Muhammad Bilal Latif
- Pathology Advanced Translational Research Unit, Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia
| | - Sudhanshu Shukla
- Pathology Advanced Translational Research Unit, Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia
| | - Perla Mariana Del Rio Estrada
- Pathology Advanced Translational Research Unit, Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia
| | - Susan Pereira Ribeiro
- Pathology Advanced Translational Research Unit, Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia
| | - Rafick Pierre Sekaly
- Pathology Advanced Translational Research Unit, Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia.
| | - Ashish Arunkumar Sharma
- Pathology Advanced Translational Research Unit, Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia
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Immunoinformatics mapping of potential epitopes in SARS-CoV-2 structural proteins. PLoS One 2021; 16:e0258645. [PMID: 34780495 PMCID: PMC8592446 DOI: 10.1371/journal.pone.0258645] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 10/01/2021] [Indexed: 01/03/2023] Open
Abstract
All approved coronavirus disease 2019 (COVID-19) vaccines in current use are safe, effective, and reduce the risk of severe illness. Although data on the immunological presentation of patients with COVID-19 is limited, increasing experimental evidence supports the significant contribution of B and T cells towards the resolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Despite the availability of several COVID-19 vaccines with high efficacy, more effective vaccines are still needed to protect against the new variants of SARS-CoV-2. Employing a comprehensive immunoinformatic prediction algorithm and leveraging the genetic closeness with SARS-CoV, we have predicted potential immune epitopes in the structural proteins of SARS-CoV-2. The S and N proteins of SARS-CoV-2 and SARS-CoVs are main targets of antibody detection and have motivated us to design four multi-epitope vaccines which were based on our predicted B- and T-cell epitopes of SARS-CoV-2 structural proteins. The cardinal epitopes selected for the vaccine constructs are predicted to possess antigenic, non-allergenic, and cytokine-inducing properties. Additionally, some of the predicted epitopes have been experimentally validated in published papers. Furthermore, we used the C-ImmSim server to predict effective immune responses induced by the epitope-based vaccines. Taken together, the immune epitopes predicted in this study provide a platform for future experimental validations which may facilitate the development of effective vaccine candidates and epitope-based serological diagnostic assays.
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Mazouz S, Boisvert M, Abdel-Hakeem MS, Khedr O, Bruneau J, Shoukry NH. Expansion of Unique Hepatitis C Virus-Specific Public CD8 + T Cell Clonotypes during Acute Infection and Reinfection. THE JOURNAL OF IMMUNOLOGY 2021; 207:1180-1193. [PMID: 34341170 DOI: 10.4049/jimmunol.2001386] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 06/09/2021] [Indexed: 11/19/2022]
Abstract
Hepatitis C virus (HCV) infection resolves spontaneously in ∼25% of acutely infected humans where viral clearance is mediated primarily by virus-specific CD8+ T cells. Previous cross-sectional analysis of the CD8+ TCR repertoire targeting two immunodominant HCV epitopes reported widespread use of public TCRs shared by different subjects, irrespective of infection outcome. However, little is known about the evolution of the public TCR repertoire during acute HCV and whether cross-reactivity to other Ags can influence infectious outcome. In this article, we analyzed the CD8+ TCR repertoire specific to the immunodominant and cross-reactive HLA-A2-restricted nonstructural 3-1073 epitope during acute HCV in humans progressing to either spontaneous resolution or chronic infection and at ∼1 y after viral clearance. TCR repertoire diversity was comparable among all groups with preferential usage of the TCR-β V04 and V06 gene families. We identified a set of 13 public clonotypes in HCV-infected humans independent of infection outcome. Six public clonotypes used the V04 gene family. Several public clonotypes were long-lived in resolvers and expanded on reinfection. By mining publicly available data, we identified several low-frequency CDR3 sequences in the HCV-specific repertoire matching human TCRs specific for other HLA-A2-restricted epitopes from melanoma, CMV, influenza A, EBV, and yellow fever viruses, but they were of low frequency and limited cross-reactivity. In conclusion, we identified 13 new public human CD8+ TCR clonotypes unique to HCV that expanded during acute infection and reinfection. The low frequency of cross-reactive TCRs suggests that they are not major determinants of infectious outcome.
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Affiliation(s)
- Sabrina Mazouz
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec, Canada
| | - Maude Boisvert
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Mohamed S Abdel-Hakeem
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.,Département de Microbiologie, Infectiologie et Immunologie, Université de Montreal, Montreal, Quebec, Canada
| | - Omar Khedr
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Julie Bruneau
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.,Département de Médecine Familiale et de Médecine d'Urgence, Université de Montréal, Montreal, Quebec, Canada; and
| | - Naglaa H Shoukry
- Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada; .,Département de Médecine, Université de Montréal, Montreal, Quebec, Canada
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7
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Bilich T, Roerden M, Maringer Y, Nelde A, Heitmann JS, Dubbelaar ML, Peter A, Hörber S, Bauer J, Rieth J, Wacker M, Berner F, Flatz L, Held S, Brossart P, Märklin M, Wagner P, Erne E, Klein R, Rammensee HG, Salih HR, Walz JS. Preexisting and Post-COVID-19 Immune Responses to SARS-CoV-2 in Patients with Cancer. Cancer Discov 2021; 11:1982-1995. [PMID: 34011563 DOI: 10.1158/2159-8290.cd-21-0191] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/15/2021] [Accepted: 05/12/2021] [Indexed: 11/16/2022]
Abstract
Patients with cancer, in particular patients with hematologic malignancies, are at increased risk for critical illness upon COVID-19. We here assessed antibody as well as CD4+ and CD8+ T-cell responses in unexposed and SARS-CoV-2-infected patients with cancer to characterize SARS-CoV-2 immunity and to identify immunologic parameters contributing to COVID-19 outcome. Unexposed patients with hematologic malignancies presented with reduced prevalence of preexisting SARS-CoV-2 cross-reactive CD4+ T-cell responses and signs of T-cell exhaustion compared with patients with solid tumors and healthy volunteers. Whereas SARS-CoV-2 antibody responses did not differ between patients with COVID-19 and cancer and healthy volunteers, intensity, expandability, and diversity of SARS-CoV-2 T-cell responses were profoundly reduced in patients with cancer, and the latter associated with a severe course of COVID-19. This identifies impaired SARS-CoV-2 T-cell immunity as a potential determinant for dismal outcome of COVID-19 in patients with cancer. SIGNIFICANCE: This first comprehensive analysis of SARS-CoV-2 immune responses in patients with cancer reports on the potential implications of impaired SARS-CoV-2 T-cell responses for understanding pathophysiology and predicting severity of COVID-19, which in turn might allow for the development of therapeutic measures and vaccines for this vulnerable patient population.See related commentary by Salomé and Horowitz, p. 1877.This article is highlighted in the In This Issue feature, p. 1861.
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Affiliation(s)
- Tatjana Bilich
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
| | - Malte Roerden
- Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany.,Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Yacine Maringer
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
| | - Annika Nelde
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
| | - Jonas S Heitmann
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Marissa L Dubbelaar
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany.,Quantitative Biology Center (QBiC), University of Tübingen, Tübingen, Germany
| | - Andreas Peter
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Sebastian Hörber
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Jens Bauer
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
| | - Jonas Rieth
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
| | - Marcel Wacker
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
| | - Fiamma Berner
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland
| | - Lukas Flatz
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.,Department of Dermatology, University Hospital Tübingen, Tübingen, Germany
| | - Stefanie Held
- Department for Hematology and Oncology, University Hospital Bonn, Bonn, Germany
| | - Peter Brossart
- Department for Hematology and Oncology, University Hospital Bonn, Bonn, Germany
| | - Melanie Märklin
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
| | - Philipp Wagner
- Department of Obstetrics and Gynecology, University Hospital of Tübingen, Tübingen, Germany
| | - Eva Erne
- Department of Urology, Medical Faculty and University Hospital, Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Reinhild Klein
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Hans-Georg Rammensee
- Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), partner site Tübingen, Tübingen, Germany
| | - Helmut R Salih
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany
| | - Juliane S Walz
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany. .,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) "Image-Guided and Functionally Instructed Tumor Therapies," University of Tübingen, Tübingen, Germany.,Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology and Robert Bosch Center for Tumor Diseases (RBCT), Stuttgart, Germany
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8
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Nelde A, Bilich T, Heitmann JS, Maringer Y, Salih HR, Roerden M, Lübke M, Bauer J, Rieth J, Wacker M, Peter A, Hörber S, Traenkle B, Kaiser PD, Rothbauer U, Becker M, Junker D, Krause G, Strengert M, Schneiderhan-Marra N, Templin MF, Joos TO, Kowalewski DJ, Stos-Zweifel V, Fehr M, Rabsteyn A, Mirakaj V, Karbach J, Jäger E, Graf M, Gruber LC, Rachfalski D, Preuß B, Hagelstein I, Märklin M, Bakchoul T, Gouttefangeas C, Kohlbacher O, Klein R, Stevanović S, Rammensee HG, Walz JS. SARS-CoV-2-derived peptides define heterologous and COVID-19-induced T cell recognition. Nat Immunol 2020; 22:74-85. [PMID: 32999467 DOI: 10.1038/s41590-020-00808-x] [Citation(s) in RCA: 433] [Impact Index Per Article: 86.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 09/11/2020] [Indexed: 12/14/2022]
Abstract
T cell immunity is central for the control of viral infections. To characterize T cell immunity, but also for the development of vaccines, identification of exact viral T cell epitopes is fundamental. Here we identify and characterize multiple dominant and subdominant SARS-CoV-2 HLA class I and HLA-DR peptides as potential T cell epitopes in COVID-19 convalescent and unexposed individuals. SARS-CoV-2-specific peptides enabled detection of post-infectious T cell immunity, even in seronegative convalescent individuals. Cross-reactive SARS-CoV-2 peptides revealed pre-existing T cell responses in 81% of unexposed individuals and validated similarity with common cold coronaviruses, providing a functional basis for heterologous immunity in SARS-CoV-2 infection. Diversity of SARS-CoV-2 T cell responses was associated with mild symptoms of COVID-19, providing evidence that immunity requires recognition of multiple epitopes. Together, the proposed SARS-CoV-2 T cell epitopes enable identification of heterologous and post-infectious T cell immunity and facilitate development of diagnostic, preventive and therapeutic measures for COVID-19.
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Affiliation(s)
- Annika Nelde
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Tatjana Bilich
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Jonas S Heitmann
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Yacine Maringer
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Helmut R Salih
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany
| | - Malte Roerden
- Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.,Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Maren Lübke
- Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
| | - Jens Bauer
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
| | - Jonas Rieth
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
| | - Marcel Wacker
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
| | - Andreas Peter
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Sebastian Hörber
- Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Bjoern Traenkle
- NMI, Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Philipp D Kaiser
- NMI, Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Ulrich Rothbauer
- NMI, Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany.,Pharmaceutical Biotechnology, University of Tübingen, Tübingen, Germany
| | - Matthias Becker
- NMI, Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Daniel Junker
- NMI, Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Gérard Krause
- Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.,TWINCORE GmbH, Centre for Experimental and Clinical Infection Research, a joint venture of the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.,German Center for Infection Research, Braunschweig, Germany
| | - Monika Strengert
- Department of Epidemiology, Helmholtz Centre for Infection Research, Braunschweig, Germany.,TWINCORE GmbH, Centre for Experimental and Clinical Infection Research, a joint venture of the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany
| | | | - Markus F Templin
- NMI, Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | - Thomas O Joos
- NMI, Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Germany
| | | | | | - Michael Fehr
- Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany
| | - Armin Rabsteyn
- Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.,Department of General Pediatrics, Oncology/Hematology, University Children's Hospital Tübingen, Tübingen, Germany
| | - Valbona Mirakaj
- Department of Anesthesia and Intensive Care Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Julia Karbach
- Department of Oncology and Hematology, Krankenhaus Nordwest, Frankfurt, Germany
| | - Elke Jäger
- Department of Oncology and Hematology, Krankenhaus Nordwest, Frankfurt, Germany
| | - Michael Graf
- Applied Bioinformatics, Center for Bioinformatics and Department of Computer Science, University of Tübingen, Tübingen, Germany
| | - Lena-Christin Gruber
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
| | - David Rachfalski
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Beate Preuß
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Ilona Hagelstein
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Melanie Märklin
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany
| | - Tamam Bakchoul
- Institute for Clinical and Experimental Transfusion Medicine, University Hospital Tübingen, Tübingen, Germany
| | - Cécile Gouttefangeas
- Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany
| | - Oliver Kohlbacher
- Applied Bioinformatics, Center for Bioinformatics and Department of Computer Science, University of Tübingen, Tübingen, Germany.,Institute for Bioinformatics and Medical Informatics, University of Tübingen, Tübingen, Germany.,Biomolecular Interactions, Max-Planck-Institute for Developmental Biology, Tübingen, Germany.,Institute for Translational Bioinformatics, University Hospital Tübingen, Tübingen, Germany
| | - Reinhild Klein
- Department of Hematology, Oncology, Clinical Immunology and Rheumatology, University Hospital Tübingen, Tübingen, Germany
| | - Stefan Stevanović
- Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany
| | - Hans-Georg Rammensee
- Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany.,Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.,German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site Tübingen, Tübingen, Germany
| | - Juliane S Walz
- Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Germany. .,Institute for Cell Biology, Department of Immunology, University of Tübingen, Tübingen, Germany. .,Cluster of Excellence iFIT (EXC2180) 'Image-Guided and Functionally Instructed Tumor Therapies', University of Tübingen, Tübingen, Germany.
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9
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Balz K, Trassl L, Härtel V, Nelson PP, Skevaki C. Virus-Induced T Cell-Mediated Heterologous Immunity and Vaccine Development. Front Immunol 2020; 11:513. [PMID: 32296430 PMCID: PMC7137989 DOI: 10.3389/fimmu.2020.00513] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 03/06/2020] [Indexed: 12/15/2022] Open
Abstract
Heterologous immunity (H.I.) is a consequence of an encounter with a specific antigen, which can alter the subsequent immune response to a different antigen. This can happen at the innate immune system level—often called trained immunity or innate immune memory—and/or at the adaptive immune system level involving T memory cells and antibodies. Viruses may also induce T cell-mediated H.I., which can confer protection or drive immunopathology against other virus subtypes, related or unrelated viruses, other pathogens, auto- or allo-antigens. It is important to understand the underlying mechanisms for the development of antiviral “universal” vaccines and broader T cell responses rather than just subtype-specific antibody responses as in the case of influenza. Furthermore, knowledge about determinants of vaccine-mediated H.I. may inform public health policies and provide suggestions for repurposing existing vaccines. Here, we introduce H.I. and provide an overview of evidence on virus- and antiviral vaccine-induced T cell-mediated cross-reactive responses. We also discuss the factors influencing final clinical outcome of virus-mediated H.I. as well as non-specific beneficial effects of live attenuated antiviral vaccines such as measles and vaccinia. Available epidemiological and mechanistic data have implications both for the development of new vaccines and for personalized vaccinology, which are presented. Finally, we formulate future research priorities and opportunities.
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Affiliation(s)
- Kathrin Balz
- German Center for Lung Research (DZL), Institute of Laboratory Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps University Marburg, Marburg, Germany
| | - Lilith Trassl
- German Center for Lung Research (DZL), Institute of Laboratory Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps University Marburg, Marburg, Germany
| | - Valerie Härtel
- German Center for Lung Research (DZL), Institute of Laboratory Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps University Marburg, Marburg, Germany
| | - Philipp P Nelson
- German Center for Lung Research (DZL), Institute of Laboratory Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps University Marburg, Marburg, Germany
| | - Chrysanthi Skevaki
- German Center for Lung Research (DZL), Institute of Laboratory Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Philipps University Marburg, Marburg, Germany
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10
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Balamurugan A, Ng HL, Yang OO. Cross-Reactivity against Multiple HIV-1 Epitopes Is Characteristic of HIV-1-Specific Cytotoxic T Lymphocyte Clones. J Virol 2018; 92:e00617-18. [PMID: 29899094 PMCID: PMC6069174 DOI: 10.1128/jvi.00617-18] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 06/05/2018] [Indexed: 11/20/2022] Open
Abstract
Although a high level of promiscuity for heterologous epitopes is believed to exist for cellular immunity, limited data explore this issue for human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T lymphocyte (CTL) responses. Here, we found an unexpected degree of heterologous cross-reactivity against HIV-1 epitopes, in addition to the targeted index epitope. Most CTL clones screened cross-reacted against other known HIV-1 epitopes of the same major histocompatibility complex type I (MHC-I) restriction, up to 40% of tested nonindex epitopes in some cases. The observed cross-reactivity was universally lower avidity than recognition of the index epitope when examined for several A*02- and B*57-restricted CTL clones, demonstrating that the high concentrations of exogenous epitope typically used for screening of CTL responses are prone to detect such cross-reactivity spuriously. In agreement with this, we found that these cross-reactive responses do not appear to mediate CTL activity against HIV-1-infected cells. Overall, our data indicate that low-level cross-reactivity is remarkably common for HIV-1-specific CTLs. The role of this phenomenon is unclear, but low-avidity interactions have been shown to foster homeostatic proliferation of memory T cells.IMPORTANCE This study raises two issues related to HIV-1-specific CTL responses. These are key immune responses that retard disease progression in infected persons that are highly relevant to immunotherapies and vaccines for HIV-1. First, we make the novel observation that these responses are promiscuous and that CTLs targeting one epitope may cross-recognize other, completely distinct epitopes in the virus. While these are low-avidity interactions that do not appear to contribute directly to the antiviral activity of CTLs, this raises interesting biologic implications regarding the purpose of the phenomenon, such as providing a stimulus for these responses to persist long term. Second, the data raise a technical caveat to detection of CTL responses against particular epitopes, suggesting that some methodologies may unintentionally detect cross-reactivity and overestimate responses against an epitope.
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Affiliation(s)
- Arumugam Balamurugan
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California USA
- UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, California, USA
| | - Hwee L Ng
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California USA
- UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, California, USA
| | - Otto O Yang
- Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California USA
- UCLA AIDS Institute, University of California, Los Angeles, Los Angeles, California, USA
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA
- AIDS Healthcare Foundation, Los Angeles, California, USA
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11
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Pohlmeyer CW, Laskey SB, Beck SE, Xu DC, Capoferri AA, Garliss CC, May ME, Livingston A, Lichmira W, Moore RD, Leffell MS, Butler NJ, Thorne JE, Flynn JA, Siliciano RF, Blankson JN. Cross-reactive microbial peptides can modulate HIV-specific CD8+ T cell responses. PLoS One 2018; 13:e0192098. [PMID: 29466365 PMCID: PMC5821448 DOI: 10.1371/journal.pone.0192098] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 01/02/2018] [Indexed: 11/19/2022] Open
Abstract
Heterologous immunity is an important aspect of the adaptive immune response. We hypothesized that this process could modulate the HIV-1-specific CD8+ T cell response, which has been shown to play an important role in HIV-1 immunity and control. We found that stimulation of peripheral blood mononuclear cells (PBMCs) from HIV-1-positive subjects with microbial peptides that were cross-reactive with immunodominant HIV-1 epitopes resulted in dramatic expansion of HIV-1-specific CD8+ T cells. Interestingly, the TCR repertoire of HIV-1-specific CD8+ T cells generated by ex vivo stimulation of PBMCs using HIV-1 peptide was different from that of cells stimulated with cross-reactive microbial peptides in some HIV-1-positive subjects. Despite these differences, CD8+ T cells stimulated with either HIV-1 or cross-reactive peptides effectively suppressed HIV-1 replication in autologous CD4+ T cells. These data suggest that exposure to cross-reactive microbial antigens can modulate HIV-1-specific immunity.
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Affiliation(s)
- Christopher W. Pohlmeyer
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Sarah B. Laskey
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Sarah E. Beck
- Department of Molecular and Comparative Pathobiology. Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Daniel C. Xu
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Adam A. Capoferri
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Caroline C. Garliss
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Megan E. May
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Alison Livingston
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Walt Lichmira
- Spondylitis Association of America, Philadelphia, Pennsylvania United States of America
| | - Richard D. Moore
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - M. Sue Leffell
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Nicholas J. Butler
- Department of Ophthalmology. Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Jennifer E. Thorne
- Department of Ophthalmology. Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - John A. Flynn
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Robert F. Siliciano
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Howard Hughes Medical Institute, Baltimore, Maryland, United States of America
| | - Joel N. Blankson
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Molecular and Comparative Pathobiology. Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- * E-mail:
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12
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Hepatitis C virus infection from the perspective of heterologous immunity. Curr Opin Virol 2016; 16:41-48. [DOI: 10.1016/j.coviro.2016.01.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2015] [Accepted: 01/08/2016] [Indexed: 01/14/2023]
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13
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Daniel V, Scherer S, Sadeghi M, Terness P, Huth-Kühne A, Opelz G. HIV-Specific CD8(+) T Lymphocytes in Blood of Long-Term HIV-Infected Hemophilia Patients. Biores Open Access 2013; 2:399-411. [PMID: 24380050 PMCID: PMC3869412 DOI: 10.1089/biores.2013.0034] [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] [Indexed: 11/13/2022] Open
Abstract
Hemophilia patients infected with human immunodeficiency virus (HIV) 30 years ago show increased proportions of activated CD8+DR+ blood lymphocytes. We hypothesized that this might indicate a cellular immune response directed against HIV and might be the reason for long-term clinical stability of these patients. CD8+ peripheral blood lymphocytes (PBL) reactive with six HIV and two cytomegalovirus (CMV) pentamers were determined in heparinized whole blood. Additional lymphocyte subsets as well as plasma cytokines and HIV-1 load were studied. Long-term HIV-infected hemophilia patients with (n=15) or without (n=33) currently detectable HIV-1 load in the plasma showed higher proportions of CD8+ lymphocytes reactive with HIV (p<0.001) and CMV pentamers (p=0.010) than healthy individuals. The cellular anti-HIV response tended to be stronger and more polyclonal in patients during periods of viral replication than in patients with retroviral quiescence (p=0.077). Anti-HIV CD8+ lymphocyte responses were strongest in patients with high counts of activated CD8+DR+ T (r=0.353; p=0.014) and low CD19+ B lymphocyte counts (r=−0.472; p=0.001). Patients with or without HIV-1 viral load showed normal Th1 and Th2 plasma cytokine levels and high plasma interleukin-6 (versus healthy controls, p=0.001) and tumor necrosis factor-α (p=0.020). Hemophilia patients who have been living with HIV for more than 30 years showed a polyclonal CD8+ T-cell response against HIV and CMV. This cellular antiviral immune response was strongest during periods of HIV-1 replication and remained detectable during periods of HIV-1 quiescence. We hypothesize that the consistent cellular anti-HIV-1 response in combination with highly active antiretroviral therapy ensures stability and survival of these chronically HIV-1–infected hemophilia patients.
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Affiliation(s)
- Volker Daniel
- Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg , Heidelberg, Germany
| | - Sabine Scherer
- Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg , Heidelberg, Germany
| | - Mahmoud Sadeghi
- Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg , Heidelberg, Germany
| | - Peter Terness
- Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg , Heidelberg, Germany
| | | | - Gerhard Opelz
- Department of Transplantation Immunology, Institute of Immunology, University of Heidelberg , Heidelberg, Germany
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14
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Petrova G, Ferrante A, Gorski J. Cross-reactivity of T cells and its role in the immune system. Crit Rev Immunol 2012; 32:349-72. [PMID: 23237510 DOI: 10.1615/critrevimmunol.v32.i4.50] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
T-cell receptors recognize peptides presented by the major histocompatibility complex (MHC) on the surface of antigen-presenting cells (APC). The ability of the T-cell receptor (TCR) to recognize more than one peptide-MHC structure defines cross-reactivity. Cross-reactivity is a documented phenomenon of the immune system whose importance is still under investigation. There are a number of rational arguments for cross-reactivity. These include the discrepancy between the theoretical high number of pathogen-derived peptides and the lower diversity of the T-cell repertoire, the need for recognition of escape variants, and the intrinsic low affinity of this receptor-ligand pair. However, quantifying the phenomenon has been difficult, and its immunological importance remains unknown. In this review, we examined the cases for and against an important role for cross reactivity. We argue that it may be an essential feature of the immune system from the point of view of biological robustness.
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Affiliation(s)
- Galina Petrova
- The Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin 53226, USA
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15
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MacParland SA, Vali B, Ostrowski MA. Immunopathogenesis of HIV/hepatitis C virus coinfection. Future Virol 2011. [DOI: 10.2217/fvl.11.80] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
As a result of shared infection routes, approximately 25% of individuals infected with HIV in North America are also infected with hepatitis C virus (HCV). In the setting of HIV coinfection, the course of HCV disease is more aggressive, resulting in higher HCV viral loads and a more rapid progression of liver pathology. With the success of HAART, HCV-related end-stage liver disease has become a leading cause of morbidity and mortality in HIV/HCV-coinfected patients. In this article, we will discuss recent studies examining the immune response during HIV and HCV coinfection, focusing on alterations or dysfunctions in virus-specific T-cell responses that may play a role in the immunopathogenesis of HIV/HCV coinfection. Summarizing the impact of HIV coinfection on HCV-specific T-cell immunity and highlighting some of the proposed mechanisms of T-cell dysfunction in HIV/HCV-coinfected individuals may uncover information that could lead to new treatment strategies for these patients experiencing accelerated liver disease and generally poorer outcomes than their HCV-monoinfected counterparts.
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Affiliation(s)
| | - Bahareh Vali
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Mario A Ostrowski
- Department of Immunology, University of Toronto, Toronto, ON, Canada; University of Toronto, Medical Sciences Building, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
- Institute of Medical Science, University of Toronto, Toronto, ON, Canada
- Clinical Sciences Division, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute at St Michael’s Hospital, Toronto, ON, Canada
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