Antigen Presentation Impairment of HLA Class I-Restricted Associated
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NK Cell Memory to Cytomegalovirus: Implications for Vaccine Development
Review NK Cell Memory to Cytomegalovirus: Implications for Vaccine Development Calum Forrest 1 , Ariane Gomes 1 , Matthew Reeves 1,* and Victoria Male 2,* 1 Institute of Immunity & Transplantation, UCL, Royal Free Campus, London NW3 2PF, UK; [email protected] (C.F.); [email protected] (A.G.) 2 Department of Metabolism, Digestion and Reproduction, Imperial College London, Chelsea and Westminster Campus, London SW10 9NH, UK * Correspondence: [email protected] (M.R.); [email protected] (V.M.) Received: 24 June 2020; Accepted: 15 July 2020; Published: 20 July 2020 Abstract: Natural killer (NK) cells are innate lymphoid cells that recognize and eliminate virally-infected and cancerous cells. Members of the innate immune system are not usually considered to mediate immune memory, but over the past decade evidence has emerged that NK cells can do this in several contexts. Of these, the best understood and most widely accepted is the response to cytomegaloviruses, with strong evidence for memory to murine cytomegalovirus (MCMV) and several lines of evidence suggesting that the same is likely to be true of human cytomegalovirus (HCMV). The importance of NK cells in the context of HCMV infection is underscored by the armory of NK immune evasion genes encoded by HCMV aimed at subverting the NK cell immune response. As such, ongoing studies that have utilized HCMV to investigate NK cell diversity and function have proven instructive. Here, we discuss our current understanding of NK cell memory to viral infection with a focus on the response to cytomegaloviruses. We will then discuss the implications that this will have for the development of a vaccine against HCMV with particular emphasis on how a strategy that can harness the innate immune system and NK cells could be crucial for the development of a vaccine against this high-priority pathogen. -
Case of the Anti HIV-1 Antibody, B12
Spectrum of Somatic Hypermutations and Implication on Antibody Function: Case of the anti HIV-1 antibody, b12 Mesfin Mulugeta Gewe A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2015 Reading Committee: Roland Strong, Chair Nancy Maizels Jessica A. Hamerman Program Authorized to Offer Degree: Molecular and Cellular Biology i ii ©Copyright 2015 Mesfin Mulugeta Gewe iii University of Washington Abstract Spectrum of Somatic Hypermutations and Implication on Antibody Function: Case of the anti HIV-1 antibody, b12 Mesfin Mulugeta Gewe Chair of the Supervisory Committee: Roland Strong, Full Member Fred Hutchinson Cancer Research Center Sequence diversity, ability to evade immune detection and establishment of human immunodeficiency virus type 1 (HIV-1) latent reservoirs present a formidable challenge to the development of an HIV-1 vaccine. Structure based vaccine design stenciled on infection elicited broadly neutralizing antibodies (bNAbs) is a promising approach, in some measure to circumvent existing challenges. Understanding the antibody maturation process and importance of the high frequency mutations observed in anti-HIV-1 broadly neutralizing antibodies are imperative to the success of structure based vaccine immunogen design. Here we report a biochemical and structural characterization for the affinity maturation of infection elicited neutralizing antibodies IgG1 b12 (b12). We investigated the importance of affinity maturation and mutations accumulated therein in overall antibody function and their potential implications to vaccine development. Using a panel of point iv reversions, we examined relevance of individual amino acid mutations acquired during the affinity maturation process to deduce the role of somatic hypermutation in antibody function. -
Development of VHH- and Antibody- Based
Development of VHH- and Antibody- based Imaging and Diagnostic Tools by Zeyang Li Bachelor of Science in Biochemistry University of Wisconsin-Madison, WI, 2011 Submitted to the Department of Chemistry In Partial Fulfilment of the requirement for the Degree of Doctor of Philosophy at the Massachusetts Institute of Technology June 2018 2018 Massachusetts Institute of Technology All rights reserved Signature redacted Signature of Author........ Department of Chemistry 21 May 2018 Certified by.....................Signature redacted Hidde Ploegh OF TECHNOLOGY Senior Investigator Program in Cellular and Molecular Medicine JUN 2 0 Z018 At Boston Children's Hospital LIBRARIES ARCHIVES Signature redacted A cce pted by ....... .......................................... Robert W. Field Haslam and Dewey Professor of Chemistry Chairman, Departmental Committee for Graduate students This doctoral thesis has been examined by a committee of the Department of Chemistry as follows: ............................Signature redacted ----- Barbara Imperiali Class of 1922 Professor of Biology and Chemistry MacVicar Faculty Fellow Thesis Committee Chair Signature redacted Hidde Ploegh Senior Investigator Program in Cellular and Molecular Medicine Boston Children's Hospital / Z" Thes;Supervisor Signature redacted Bradley L. Pentelute Pfizer-Laubach Career Development Professor of Chemistry Abstract The immune system distinguishes self from non-self to combat pathogenic incursions. Evasion tactics deployed by viruses, microbes, or malignant cells may impede an adequate response. In such cases, therapeutic interventions aid in the elimination of pathogens and the restoration of physiological homeostasis. A major road block in the development of such therapies is the reliance on imperfect detection methods to identify site(s) of infection, or to monitor immune cell recruitment to sites of infection or inflammation in vivo. -
The T Cell Repertoire Specific for the IE-1 Protein of Human Cytomegalovirus: Diversity, Function and Evasion
Dissertation zur Erlangung des Doktorgrades der Fakultät für Chemie und Pharmazie der Ludwig-Maximilians-Universität München The T cell repertoire specific for the IE-1 protein of human cytomegalovirus: diversity, function and evasion von Stefanie Maria Ameres aus Deggendorf, Deutschland 2012 Erklärung Diese Dissertation wurde im Sinne von §7 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Wolfgang Hammerschmidt betreut und von Herrn Prof. Dr. Horst Domdey vor der Fakultät für Chemie und Pharmazie vertreten. Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, den 03.07.2012 Stefanie Ameres Dissertation eingereicht am 03.07.2012 1. Gutachter: Prof. Dr. Horst Domdey 2. Gutachter: Prof. Dr. Wolfgang Hammerschmidt Mündliche Prüfung am 28.01.2013 Teile dieser Arbeit werden/wurden wie folgt veröffentlicht: Ameres, S., J. Mautner, F. Schlott, M. Neuenhahn, D.H. Busch, B. Plachter, and A. Moosmann. Antigen Presentation to an Immunodominant Population of HLA-C-Restricted T Cells Resists Cytomegalovirus Immunoevasion. 2nd revision PLOS Pathogens Hesse, J., S. Ameres, K. Besold, S. Krauter, A. Moosmann, and B. Plachter. Suppression of CD8+ T-cell recognition in the immediate-early phase of human cytomegalovirus infection. Epub oct 2012. J. Gen. Virol. Teile dieser Arbeit wurden im Rahmen der Dissertation wie folgt präsentiert: May 3rd–4th, 2012 DFG SFB-TR36 Symposium "Adoptive T Cell Therapy" Berlin, Germany Talk: "CD8+ T cells overcome HCMV immunoevasion dependent on their HLA restriction" Dec. 5th–7th, 2011 DFG SFB-TR36 Retreat "Principles and Applications of Wildbad Kreuth, Adoptive T Cell therapy" Germany Talk: "CD8+ T cells defeat HCMV immunoevasins dependent on MHC restriction" May 14th–17th, 2011 13th International CMV/Betaherpesvirus Workshop Nürnberg, Germany Poster 1: "Preferential T cell control of HCMV infection through HLA-C" Poster 2: "HCMV IE-1 is recognized by a diverse repertoire of CD4+ Tcells" Oct. -
Structural Basis of Mouse Cytomegalovirus M152/Gp40 Interaction with Rae1γ Reveals a Paradigm for MHC/MHC Interaction in Immune
Structural basis of mouse cytomegalovirus m152/gp40 PNAS PLUS interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion Rui Wanga, Kannan Natarajana, Maria Jamela R. Revillezaa, Lisa F. Boyda, Li Zhia,1, Huaying Zhaob, Howard Robinsonc, and David H. Marguliesa,2 aMolecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; bDynamics of Macromolecular Assembly Section, Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomolecular Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20892; and cNational Synchrotron Light Source, Brookhaven National Laboratories, Upton, NY 11973 Edited by K. Christopher Garcia, Stanford University, Stanford, CA, and approved October 24, 2012 (received for review August 17, 2012) Natural killer (NK) cells are activated by engagement of the NKG2D NKG2D ligands, we examined the binding of the MCMV m152 receptor with ligands on target cells stressed by infection or glycoprotein to its RAE1 ligands. Our previous studies investigated tumorigenesis. Several human and rodent cytomegalovirus (CMV) the quantitative interaction of m152 with different RAE1 isoforms immunoevasins down-regulate surface expression of NKG2D (21). Here we report the X-ray structure of the complex of m152 ligands. The mouse CMV MHC class I (MHC-I)–like m152/gp40 glyco- with RAE1γ, the confirmation of the intermolecular contacts protein down-regulates retinoic acid early inducible-1 (RAE1) observed in the crystal structure by site-directed mutagenesis and NKG2D ligands as well as host MHC-I. Here we describe the crystal in vitro binding assays, a comparison of the binding of m152 to structure of an m152/RAE1γ complex and confirm the intermolec- RAE1 and of NKG2D to RAE1, and the functional effects of ular contacts by mutagenesis. -
Cell Biology from an Immune Perspective in This Lecture We Will
Harvard-MIT Division of Health Sciences and Technology HST.176: Cellular and Molecular Immunology Course Director: Dr. Shiv Pillai Cell Biology from an Immune Perspective In this lecture we will very briefly review some aspects of cell biology which are required as background knowledge in order to understand how the immune system works. These will include: 1. A brief overview of protein trafficking 2. Signal transduction 3. The cell cycle Some of these issues will be treated in greater depth in later lectures. Protein Trafficking/The Secretory Pathway: From an immune perspective the secretory compartment and structures enclosed by vesicles are “seen” in different ways from proteins that reside in the cytosol or the nucleus. We will briefly review the secretory and endocytic pathways and discuss the biogenesis of membrane proteins. Some of the issues that will be discussed are summarized in Figures 1-3. Early endosomes Late endosomes Lysosomes Golgi Vesiculo-Tubular Compartment ER Figure 1. An overview of the secretory pathway Early endosomes Late endosomes Multivesicular and multilamellar bodies Golgi ER Proteasomes Figure 2. Protein degradation occurs mainly in lysosomes and proteasomes Proteins that enter the cell from the environment are primarily degraded in lysosomes. Most cytosolic and nuclear proteins are degraded in organelles called proteasomes. Intriguingly these two sites of degradation are each functionally linked to distinct antigen presentation pathways, different kinds of MHC molecules and the activation of different categories of T cells. Integral membrane proteins maybe inserted into the membrane in a number of ways, the two most common of these ways being considered in Figure 3. -
Optimized Fluorescent Labeling to Identify Memory B Cells Specific for Neisseria Meningitidis Serogroup B Vaccine Antigens Ex Vivo
Optimized fluorescent labeling to identify memory B cells specific for Neisseria meningitidis serogroup B vaccine antigens ex vivo The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Nair, Nitya, Ludovico Buti, Elisa Faenzi, Francesca Buricchi, Sandra Nuti, Chiara Sammicheli, Simona Tavarini, et al. “ Optimized Fluorescent Labeling to Identify Memory B Cells Specific for Neisseria Meningitidis Serogroup B Vaccine Antigens Ex Vivo .” Immun. Inflamm. Dis. 1, no. 1 (October 2013): 3–13. As Published http://dx.doi.org/10.1002/iid3.3 Publisher Wiley Blackwell Version Final published version Citable link http://hdl.handle.net/1721.1/92523 Terms of Use Creative Commons Attribution Detailed Terms http://creativecommons.org/licenses/by/3.0/ ORIGINAL RESEARCH Optimized fluorescent labeling to identify memory B cells specific for Neisseria meningitidis serogroup B vaccine antigens ex vivo Nitya Nair1†, Ludovico Buti1,2‡, Elisa Faenzi1, Francesca Buricchi1, Sandra Nuti1, Chiara Sammicheli1, Simona Tavarini1, Maximilian W.L. Popp2,3,4, Hidde Ploegh2,4, Francesco Berti1, Mariagrazia Pizza1, Flora Castellino1, Oretta Finco1, Rino Rappuoli1, Giuseppe Del Giudice1, Grazia Galli1, & Monia Bardelli1 1Novartis Vaccines & Diagnostics, Siena, Italy 2Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 3University of Rochester, School of Medicine & Dentistry, Rochester, New York 4Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts Keywords Abstract Antigen-specific memory B cells, flow cytometry, Neisseria meningitidis MenB, Antigen-specific memory B cells generate anamnestic responses and high affinity sortagging, vaccination antibodies upon re-exposure to pathogens. Attempts to isolate rare antigen- specific memory B cells for in-depth functional analysis at the single-cell level have Correspondence been hindered by the lack of tools with adequate sensitivity. -