DOCSLIB.ORG

Regulation of Effective B Cell Responses to Chronic Infection

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Regulation of Effective B Cell Responses to Chronic Infection University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2019 Regulation Of Effective B Cell Responses To Chronic Infection Ryan Phillip Staupe University of Pennsylvania Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Allergy and Immunology Commons, Immunology and Infectious Disease Commons, and the Medical Immunology Commons Recommended Citation Staupe, Ryan Phillip, "Regulation Of Effective B Cell Responses To Chronic Infection" (2019). Publicly Accessible Penn Dissertations. 3637. https://repository.upenn.edu/edissertations/3637 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/3637 For more information, please contact [email protected]. Regulation Of Effective B Cell Responses To Chronic Infection Abstract Chronic viral infections disrupt B cell responses leading to impaired affinity maturation and delayed control of viremia. Previous studies have identified early pre-germinal center (GC) B cell attrition but the impact of chronic infections on B cell fate decisions in GCs remains poorly understood. To address this question, we used single-cell transcriptional profiling of virus-specific GC B cells during chronic viral infection to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC checkpoint disrupted by chronic infection specifically at the point of dark onez re-entry. During chronic viral infection, virus-specific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MB) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Mechanistically, persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal differentiation. Thus, these studies define GC defects during chronic viral infection and identify a critical GC checkpoint that is short- circuited, preventing optimal maturation of humoral immunity. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Immunology First Advisor E. John Wherry Keywords B cells, Cellular differentiation, Chronic viral infection, Germinal Center, Inflammation, Single cell RNAseq Subject Categories Allergy and Immunology | Immunology and Infectious Disease | Medical Immunology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/3637 REGULATION OF EFFECTIVE B CELL RESPONSES TO CHRONIC INFECTION Ryan P. Staupe A DISSERTATION in Immunology Presented to the Faculties oF the University oF Pennsylvania in Partial FulFillment oF the Requirements For the Degree oF Doctor oF Philosophy 2019 Supervisor oF Dissertation _____________________ E. John Wherry, Ph.D. Chair, Department oF Systems Pharmacology and Translational Therapeutics, Richard and Barbara SchiFFrin President’s Distinguished ProFessor Graduate Group Chairperson _______________________ David Michael Allman, Ph.D. ProFessor oF Pathology and Laboratory Medicine Dissertation Committee Michael Paul Cancro, Ph.D., ProFessor oF Pathology and Laboratory Medicine David Michael Allman, Ph.D., ProFessor oF Pathology and Laboratory Medicine Daniel Douek, M.D., Ph.D., ChieF, Human Immunology Section, VRC, NIAID, NIH Jorge Henao-Mejia, M.D., Ph.D., Assistant ProFessor oF Pathology and Laboratory Medicine Christopher A. Hunter, B.Sc, Ph.D., Distinguished ProFessor oF Pathobiology REGULATION OF EFFECTIVE B CELL RESPONSES TO CHRONIC INFECTION COPYRIGHT 2019 Ryan Phillip Staupe This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 4.0 License To view a copy oF this license, visit https://creativecommons.org/licenses/by-nc-sa/4.0/us/ ACKNOWLEDGMENTS My path through graduate school has been one oF tremendous personal and scientiFic growth that would not have been possible without the support oF those around me and, in particular, my mentor E. John Wherry. Thank you John For always pushing me to think deeper, edit more, take risks, and be generous with my time. Your passion For science and clarity oF thought has been crucial to my growth as a scientist. Next, I would like to thank the members oF my thesis committee For their invaluable advice and support over the past Few years. Thank you Michael Cancro, David Allman, Daniel Douek, Jorge Henao-Mejia, and Christopher Hunter. Your guidance has been instrumental For shaping the science contained within this dissertation. A special thank you to the Penn IGG program For providing a rewarding and challenging environment in which to learn and grow as a scientist. In particular, I’d like to thank Mary Taylor For going above and beyond in ensuring that our lives run smoothly. Your hard work and dedication are something to be emulated. Nothing in this dissertation would have been achieved iF not For the incredible and dynamic members oF the Wherry lab, both past and present, who have made coming to lab something I look Forward to daily. In particular, I’d like to thank Pam Odorizzi and Kristen Pauken For showing me the ropes at a time when I truly knew nothing. Thank you to Sasi Manne, Josephine Giles, Ramin Herati, and Amy Baxter For your endless patience, scientiFic insight, and Friendship over the years. Thank you to Omar Khan, JenniFer Wu, Zeyu Chen, and Jane Huang For being the most incredible group oF graduate students anywhere and For all the laughs along the way. Finally, I’d like to thank Laura Vella who without her encouragement, patience, and generosity none oF this work would have been possible. Finally, I’d like to thank my Family For their love, support, and guidance during this journey. To my parents, thank you For instilling within me a drive and a passion For learning. Your hard work, dedication, and sacriFices over the years have allowed me to become the person I am today and For that I will be eternally thankful. To my wiFe Jenab, thank you For being my rock. Without your kindness, inspiration, and support over the years I would not be at this point today. I love you more than I can possibly put into words. iii ABSTRACT REGULATION OF EFFECTIVE B CELL RESPONSES TO CHRONIC INFECTION Ryan P. Staupe E. John Wherry Chronic viral inFections disrupt B cell responses leading to impaired aFFinity maturation and delayed control oF viremia. Previous studies have identiFied early pre-germinal center (GC) B cell attrition but the impact oF chronic inFections on B cell Fate decisions in GCs remains poorly understood. To address this question, we used single-cell transcriptional proFiling oF virus-speciFic GC B cells during chronic viral inFection to test the hypothesis that chronic viral inFection disrupted GC B cell Fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC checkpoint disrupted by chronic inFection speciFically at the point oF dark zone re-entry. During chronic viral inFection, virus-speciFic GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MB) Fates at the expense oF continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Mechanistically, persisting antigen and inFlammation independently drove Facets oF dysregulation, with a key role For inFlammation in directing premature terminal diFFerentiation. Thus, these studies deFine GC deFects during chronic viral iv inFection and identiFy a critical GC checkpoint that is short-circuited, preventing optimal maturation oF humoral immunity. v TABLE OF CONTENTS ACKNOWLEDGMENTS ................................................................................................. iii ABSTRACT .................................................................................................................. iv LIST OF FIGURES ........................................................................................................ viii CHAPTER 1: Introduction ............................................................................................. 1 1.1 Chronic viral infections: a unique challenge for humoral immunity ................................ 1 1.2 Humoral immune responses to acute infection and immunization ................................. 3 1.2.1 Initiation of the B cell response .................................................................................................... 4 1.2.2 Establishment of the germinal center response ........................................................................... 7 1.2.3 Germinal center response ............................................................................................................ 8 1.3 Humoral Immunity to chronic viral infections ............................................................... 15 1.4 LCMV model system as a tool to mechanistically study chronic viral infections ............ 17 CHAPTER 2: Chronic viral inFections impair virus-speciFic germinal center responses .. 22 2.1 Introduction ................................................................................................................. 22 2.2 Methods ...................................................................................................................... 24 2.2.1 Mice ............................................................................................................................................ 24 2.2.2 Viral infection ............................................................................................................................
Load more

Recommended publications
  • Type I Interferons in Anticancer Immunity
    REVIEWS Type I interferons in anticancer immunity Laurence Zitvogel1–4*, Lorenzo Galluzzi1,5–8*, Oliver Kepp5–9, Mark J. Smyth10,11 and Guido Kroemer5–9,12 Abstract | Type I interferons (IFNs) are known for their key role in antiviral immune responses. In this Review, we discuss accumulating evidence indicating that type I IFNs produced by malignant cells or tumour-infiltrating dendritic cells also control the autocrine or paracrine circuits that underlie cancer immunosurveillance. Many conventional chemotherapeutics, targeted anticancer agents, immunological adjuvants and oncolytic 1Gustave Roussy Cancer Campus, F-94800 Villejuif, viruses are only fully efficient in the presence of intact type I IFN signalling. Moreover, the France. intratumoural expression levels of type I IFNs or of IFN-stimulated genes correlate with 2INSERM, U1015, F-94800 Villejuif, France. favourable disease outcome in several cohorts of patients with cancer. Finally, new 3Université Paris Sud/Paris XI, anticancer immunotherapies are being developed that are based on recombinant type I IFNs, Faculté de Médecine, F-94270 Le Kremlin Bicêtre, France. type I IFN-encoding vectors and type I IFN-expressing cells. 4Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, F-94800 Villejuif, France. Type I interferons (IFNs) were first discovered more than Type I IFNs in cancer immunosurveillance 5Equipe 11 labellisée par la half a century ago as the factors underlying viral inter­ Type I IFNs are known to mediate antineoplastic effects Ligue Nationale contre le ference — that is, the ability of a primary viral infection against several malignancies, which is a clinically rel­ Cancer, Centre de Recherche 1 des Cordeliers, F-75006 Paris, to render cells resistant to a second distinct virus .
    [Show full text]
  • Detecting the Stable Point of Therapeutic Effect of Chronic Myeloid
    Xu et al. BMC Bioinformatics 2019, 20(Suppl 7):202 https://doi.org/10.1186/s12859-019-2738-0 RESEARCH Open Access Detecting the stable point of therapeutic effect of chronic myeloid leukemia based on dynamic network biomarkers Junhua Xu1,MinWu1, Shanshan Zhu1,JinzhiLei2 and Jie Gao1* From The 12th International Conference on Computational Systems Biology (ISB 2018) Guiyang, China. 18-21 August 2018 Abstract Background: Most researches of chronic myeloid leukemia (CML) are currently focused on the treatment methods, while there are relatively few researches on the progress of patients’ condition after drug treatment. Traditional biomarkers of disease can only distinguish normal state from disease state, and cannot recognize the pre-stable state after drug treatment. Results: A therapeutic effect recognition strategy based on dynamic network biomarkers (DNB) is provided for CML patients’ gene expression data. With the DNB criteria, the DNB with 250 genes is selected and the therapeutic effect index (TEI) is constructed for the detection of individual disease. The pre-stable state before the disease condition becomes stable is 1 month. Through functional analysis for the DNB, some genes are confirmed as key genes to affect the progress of CML patients’ condition. Conclusions: The results provide a certain theoretical direction and theoretical basis for medical personnel in the treatment of CML patients, and find new therapeutic targets in the future. The biomarkers of CML can help patients to be treated promptly and minimize drug resistance, treatment failure and relapse, which reduce the mortality of CML significantly. Keywords: Chronic myeloid leukemia (CML), Dynamic network biomarkers (DNB), Differentially expressed genes (DEGs), Therapeutic effect index (TEI), Pre-stable state, Treatment time Introduction At present, the use of ABL kinase inhibitors (e.g.
    [Show full text]
  • Mechanisms of Type-I Ifn Inhibition: Equine Herpesvirus-1 Escape from the Antiviral Effect of Type-1 Interferon Response in Host Cell
    University of Kentucky UKnowledge Theses and Dissertations--Veterinary Science Veterinary Science 2019 MECHANISMS OF TYPE-I IFN INHIBITION: EQUINE HERPESVIRUS-1 ESCAPE FROM THE ANTIVIRAL EFFECT OF TYPE-1 INTERFERON RESPONSE IN HOST CELL Fatai S. Oladunni University of Kentucky, [email protected] Author ORCID Identifier: https://orcid.org/0000-0001-5050-0183 Digital Object Identifier: https://doi.org/10.13023/etd.2019.374 Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Oladunni, Fatai S., "MECHANISMS OF TYPE-I IFN INHIBITION: EQUINE HERPESVIRUS-1 ESCAPE FROM THE ANTIVIRAL EFFECT OF TYPE-1 INTERFERON RESPONSE IN HOST CELL" (2019). Theses and Dissertations--Veterinary Science. 43. https://uknowledge.uky.edu/gluck_etds/43 This Doctoral Dissertation is brought to you for free and open access by the Veterinary Science at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Veterinary Science by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known.
    [Show full text]
  • Interferon-Alpha-Based Immunotherapies in the Treatment Of
    Zhang et al. Exp Hematol Oncol (2017) 6:20 DOI 10.1186/s40164-017-0081-6 Experimental Hematology & Oncology REVIEW Open Access Interferon‑alpha‑based immunotherapies in the treatment of B cell‑derived hematologic neoplasms in today’s treat‑to‑target era Li Zhang1,2, Yu‑Tzu Tai1*, Matthew Zhi Guang Ho1,3,4, Lugui Qiu5 and Kenneth C. Anderson1* Abstract B cell lymphoma and multiple myeloma (MM) are the most common hematological malignancies which beneft from therapeutic monoclonal antibodies (mAbs)-based immunotherapies. Despite signifcant improvement on patient outcome following the use of novel therapies for the past decades, curative treatment is unavailable for the major‑ ity of patients. For example, the 5-year survival of MM is currently less than 50%. In the 1980s, interferon-α was used as monotherapy in newly diagnosed or previously treated MM with an overall response rate of 15–20%. Noticeably, a small subset of patients who responded to long-term interferon-α further achieved sustained complete remission. Since 1990, interferon-α-containing regimens have been used as a central maintenance strategy for patients with MM. However, the systemic administration of interferon-α was ultimately limited by its pronounced toxicity. To address this, the selective mAb-mediated delivery of interferon-α has been developed to enhance specifc killing of MM and B-cell malignant cells. As such, targeted interferon-α therapy may improve therapeutic window and sustain responses, while further overcoming suppressive microenvironment. This review aims to reinforce the role of interferon-α by consolidating our current understanding of targeting interferon-α with tumor-specifc mAbs for B cell lymphoma and myeloma.
    [Show full text]
  • Wright1260921490.Pdf (1.84
    A POTENTIAL STRATEGY TO MAINTAIN HSV-1 IN A LATENT STATE: USE OF IMMUNOREGULATORY PEPTIDE MIMETICS A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science By NASRIN MAJIDI 2009 Wright State University WRIGHT STATE UNIVERSITY SCHOOL OF GRADUATE STUDIES December 7, 2009 I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY Nasrin Majidi ENTITLED. A potential strategy to maintain HSV-1 in a latent state: use of immunoregulatory peptide mimetics. BE ACCEPTED IN PARTIAL FULFILLMENT OF THE REQUIRMENTS FOR THE DEGREE OF Master of Science. ___________________________ Nancy J. Bigley, Ph.D. Thesis Director ___________________________ Barbara E. Hull, Ph.D. Program Director Committee on Final Examination _______________________ Nancy J. Bigley, Ph.D. _______________________ Barbara E. Hull, Ph.D. _______________________ Cheryl L. Conley, Ph.D. _______________________ Dean Joseph F. Thomas, Jr., Ph.D. Dean, School of Graduate Studies ABSTRACT Majidi, Nasrin. M.S., Department of Biological Sciences, Microbiology and Immunology Program, Wright State University, 2009. A potential strategy to maintain HSV-1 in a latent state: use of immunoregulatory peptide mimetics. This study reviews the role of interferon-gamma (IFN-γ) in HSV-1 latency. CD8+ T cells inhibit the reactivation of HSV-1 in trigeminal ganglia (TG) by production of IFN-γ. Although CD8+ T cells include all the cytotoxic apparatus for cytotoxicity, latently infected neuronal cells are not killed by CD8+ T cells. The CD94-NKG2a molecule on CD8+ T cells, binds to Qa-1b (a MHC class I like molecule) present on neuronal cell to inhibit CD8+ T cells cytotoxicity.
    [Show full text]
  • Β Primary Human Leukocyte Subsets to IFN- Major Differences in The
    Major Differences in the Responses of Primary Human Leukocyte Subsets to IFN- β Anette H. H. van Boxel-Dezaire, Joana A. Zula, Yaomin Xu, Richard M. Ransohoff, James W. Jacobberger and George R. This information is current as Stark of October 1, 2021. J Immunol published online 18 October 2010 http://www.jimmunol.org/content/early/2010/10/18/jimmun ol.0902314 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2010/10/19/jimmunol.090231 Material 4.DC1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 18, 2010, doi:10.4049/jimmunol.0902314 The Journal of Immunology Major Differences in the Responses of Primary Human Leukocyte Subsets to IFN-b Anette H. H. van Boxel-Dezaire,* Joana A. Zula,* Yaomin Xu,† Richard M. Ransohoff,‡ James W. Jacobberger,x and George R. Stark* Treatment of cell lines with type I IFNs activates the formation of IFN-stimulated gene factor 3 (STAT1/STAT2/IFN regulatory factor-9), which induces the expression of many genes.
    [Show full text]
  • Interferon-Alpha Promotes Immunosuppression Through IFNAR1/STAT1 Signalling in Head and Neck Squamous Cell Carcinoma
    www.nature.com/bjc ARTICLE Translational Therapeutics Interferon-alpha promotes immunosuppression through IFNAR1/STAT1 signalling in head and neck squamous cell carcinoma Hailong Ma1,2, Wenyi Yang1,2, Liming Zhang1,2, Shuli Liu1,2, Mei Zhao3, Ge Zhou3, Lizhen Wang4, Shufang Jin1,2, Zhiyuan Zhang1,2 and Jingzhou Hu1,2 BACKGROUND: An immunosuppressive microenvironment is critical for cancer initiation and progression. Whether interferon alpha (IFNα) can suppress immune and cancer cells and its involved mechanism still remain largely elusive. METHODS: We examine the expression of interferon alpha/beta receptor-1 (IFNAR1), CD8, CD56 and programmed death ligand 1 (PDL1) in head and neck squamous cell carcinomas (HNSCC). The effect of IFNα on PDL1 and programmed cell death protein 1 (PD1) expression in tumour cells and immune cells was detected in vitro and in vivo. RESULTS: Overexpression of IFNAR1, MX1 and signal transducer and activator of transcription 1 (Stat1) indicated the endogenous IFNα activation in tumour microenvironment, which correlated with immunosuppression status in HNSCC patients. Moreover, IFNα transcriptionally activated the expression of PDL1 through p-Stat1 (Tyr701) and promoted PD1 expression in immune cells through IFNAR1. The inhibition of IFNα signalling enhanced the cytotoxic activity of nature killer cells. At lastastly, we confirmed the upregulation of PDL1 and PD1 in response to IFNα treatment in both xenograft tumour models and patient-derived xenograft models. CONCLUSIONS: Our findings demonstrate that IFNα-induced PDL1 and PD1 expression is a new mechanism of immunosuppression in HNSCC, suggesting that blocking IFNα signalling may enhance the efficacy of immune checkpoint blockade. British Journal of Cancer (2019) 120:317–330; https://doi.org/10.1038/s41416-018-0352-y INTRODUCTION Interferon alpha (IFNα) is a pleiotropic cytokine belonging to the Head and neck squamous cell carcinoma (HNSCC) accounts for ~ type I IFN family that is originally described for its antiviral 90% of head and neck cancer.
    [Show full text]
  • Innate and Adaptive Signals Enhance Differentiation and Expansion of Dual-Antibody Autoreactive B Cells in Lupus
    ARTICLE DOI: 10.1038/s41467-018-06293-z OPEN Innate and adaptive signals enhance differentiation and expansion of dual-antibody autoreactive B cells in lupus Allison Sang1, Thomas Danhorn 2, Jacob N. Peterson1, Andrew L. Rankin3,4, Brian P. O’Connor1,2,5,6, Sonia M. Leach2,5, Raul M. Torres1,5 & Roberta Pelanda1,5 1234567890():,; Autoreactive B cells have a major function in autoimmunity. A small subset of B cells expressing two distinct B-cell-antigen-receptors (B2R cells) is elevated in many patients with systematic lupus erythematosus (SLE) and in the MRL(/lpr) mouse model of lupus, and is often autoreactive. Here we show, using RNAseq and in vitro and in vivo analyses, signals that are required for promoting B2R cell numbers and effector function in autoimmune mice. Compared with conventional B cells, B2R cells are more responsive to Toll-like receptor 7/9 and type I/II interferon treatment, display higher levels of MHCII and co-receptors, and depend on IL-21 for their homeostasis; moreover they expand better upon T cell-dependent antigen stimulation, and mount a more robust memory response, which are characteristics essential for enhanced (auto)immune responses. Our findings thus provide insights on the stimuli for the expansion of an autoreactive B cell subset that may contribute to the etiology of SLE. 1 Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, USA. 2 Center for Genes, Environment and Health, National Jewish Health, Denver, CO 80206, USA. 3 Inflammation and Immunology, Pfizer Research, Cambridge, MA 02140, USA. 4 Immuno- Oncology Discovery, FivePrime Therapeutics, South San Francisco, CA 94080, USA.
    [Show full text]
  • Transcriptome Analysis Reveals a Classical Interferon Signature Induced by Ifnλ4 in Human Primary Cells
    Genes and Immunity (2015) 16, 414–421 © 2015 Macmillan Publishers Limited All rights reserved 1466-4879/15 www.nature.com/gene ORIGINAL ARTICLE Transcriptome analysis reveals a classical interferon signature induced by IFNλ4 in human primary cells C Lauber1,8, G Vieyres2,8, E Terczyńska-Dyla3, Anggakusuma2, R Dijkman4, HH Gad3, H Akhtar3, R Geffers5, FWR Vondran6,7, V Thiel4, L Kaderali1, T Pietschmann2,6 and R Hartmann3 The IFNL4 gene is negatively associated with spontaneous and treatment-induced clearance of hepatitis C virus infection. The activity of IFNλ4 has an important causal role in the pathogenesis, but the molecular details are not fully understood. One possible reason for the detrimental effect of IFNλ4 could be a tissue-specific regulation of an unknown subset of genes. To address both tissue and subtype specificity in the interferon response, we treated primary human hepatocytes and airway epithelial cells with IFNα, IFNλ3 or IFNλ4 and assessed interferon mediated gene regulation using transcriptome sequencing. Our data show a surprisingly similar response to all three subtypes of interferon. We also addressed the tissue specificity of the response, and identified a subset of tissue-specific genes. However, the interferon response is robust in both tissues with the majority of the identified genes being regulated in hepatocytes as well as airway epithelial cells. Thus we provide an in-depth analysis of the liver interferon response seen over an array of interferon subtypes and compare it to the response in the lung epithelium. Genes and Immunity (2015) 16, 414–421; doi:10.1038/gene.2015.23; published online 11 June 2015 INTRODUCTION IL10R2 (IL10Rβ) chain.3,4 Expression of IFNλR1 is rather restricted, Tissue-specific responses to the different interferon (IFN) subtypes with epithelial tissues and the liver showing the most prominent 5,6 are poorly understood, and the vast majority of studies are expression in humans.
    [Show full text]
  • Type I and II Interferons in the Anti-Tumor Immune Response
    cancers Review Type I and II Interferons in the Anti-Tumor Immune Response Sarah E. Fenton 1,2, Diana Saleiro 1,2 and Leonidas C. Platanias 1,2,3,* 1 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL 60611, USA; [email protected] (S.E.F.); [email protected] (D.S.) 2 Division of Hematology-Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA 3 Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA * Correspondence: [email protected] Simple Summary: Interferons are cytokines that play key roles in the activation of cellular com- ponents of the immune response, such as dendritic cells, macrophages and T cells. Generally, these cytokines promote anti-tumor immune responses, but under some circumstances, prolonged exposure to them can lead to suppression of the immune response. This review focuses on the immunostimulatory versus immunosuppressive roles of interferons and the mechanisms mediating such effects on both malignant cells and cells of the immune system. Abstract: The interferons (IFNs) are essential components of the immune response against infec- tions and malignancies. IFNs are potent promoters of the anti-tumor response, but there is also evidence that feedback mechanisms regulated by IFNs negatively control immune responses to avoid hyper-activation and limit inflammation. This balance of responses plays an important role in cancer surveillance, immunoediting and response to anticancer therapeutic approaches. Here we review the roles of both type I and type II IFNs on the control of the immune response against malignancies in the context of effects on both malignant cells and cells of the immune system in the Citation: Fenton, S.E.; Saleiro, D.; tumor microenvironment.
    [Show full text]
  • Regulated Proteolysis of the Ifnar2 Subunit of the Interferon-Alpha Receptor
    Oncogene (2004) 23, 7076–7086 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc Regulated proteolysis of the IFNaR2 subunit of the interferon-alpha receptor Abu ZM Saleh1, Aaron T Fang1, Allison E Arch1, Divas Neupane2, Ashraf El Fiky2 and John J Krolewski*1,2,3 1Department of Pathology, College of Medicine, University of California, Irvine, CA 92697, USA; 2Department of Biological Chemistry, College of Medicine, University of California, Irvine, CA 92697, USA; 3Chao Family Comprehensive Cancer Center, College of Medicine, University of California, Irvine, CA 92697, USA The type I interferons (IFNs) bind surface receptors, modulate gene transcription (Levy and Darnell, 2002). induce JAK kinases and activate STAT transcription The JAKs bind constitutively to receptor subunits, are factors to stimulate the transcription of genes downstream activated when ligand binding dimerizes the receptor of IFN-stimulated response elements (ISREs). In this subunits and sequentially phosphorylate multiple com- study, we demonstrate that IFNaR2, a subunit of the type ponents of the signaling cascade. In the case of the type I I IFN receptor, is proteolytically cleaved in a regulated IFNs, including IFN-a and -b, ligand binding to the manner. Immunoblotting shows that multi-step cleavage IFNaR1 and IFNaR2 receptor subunits juxtaposes and occurs in response to phorbol ester (PMA) and IFN-a, activates Tyk2 and Jak1, the associated JAK kinases generating both a transmembrane ‘stub’ and the intracel- (Colamonici et al., 1994; Domanski et al., 1995; Yan lular domain (ICD), similar to Notch proteolysis. Isolated et al., 1996b). The JAKs become phosphorylated, and in membrane fractions process IFNaR2 to release the ICD.
    [Show full text]
  • Primary Chicken and Duck Endothelial Cells Display a Differential Response to Infection with Highly Pathogenic Avian Influenza Virus
    G C A T T A C G G C A T genes Article Primary Chicken and Duck Endothelial Cells Display a Differential Response to Infection with Highly Pathogenic Avian Influenza Virus Zhen Wei Marcus Tong 1,†, Anjana C. Karawita 1,2,† , Colin Kern 3, Huaijun Zhou 3 , Jane E. Sinclair 1 , Limin Yan 1, Keng Yih Chew 1, Sue Lowther 2, Lee Trinidad 2, Arjun Challagulla 2 , Karel A. Schat 4 , Michelle L. Baker 2 and Kirsty R. Short 1,5,* 1 School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Australia; [email protected] (Z.W.M.T.); [email protected] (A.C.K.); [email protected] (J.E.S.); [email protected] (L.Y.); [email protected] (K.Y.C.) 2 CSIRO, Australian Centre for Disease Preparedness, Health, and Biosecurity Business Unit, Geelong 3219, Australia; [email protected] (S.L.); [email protected] (L.T.); [email protected] (A.C.); [email protected] (M.L.B.) 3 Department of Animal Science, University of California, Davis, CA 95616, USA; [email protected] (C.K.); [email protected] (H.Z.) 4 Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA; [email protected] 5 Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane 4072, Australia * Correspondence: [email protected] † These authors contributed equally to this work. Citation: Tong, Z.W.M.; Karawita, A.C.; Kern, C.; Zhou, H.; Sinclair, J.E.; Abstract: Highly pathogenic avian influenza viruses (HPAIVs) in gallinaceous poultry are associated Yan, L.; Chew, K.Y.; Lowther, S.; Trinidad, L.; Challagulla, A.; et al.
    [Show full text]