• Login
    View Item 
    •   Home
    • UMass Chan Student Research and Publications
    • Morningside Graduate School of Biomedical Sciences
    • Morningside Graduate School of Biomedical Sciences Dissertations and Theses
    • View Item
    •   Home
    • UMass Chan Student Research and Publications
    • Morningside Graduate School of Biomedical Sciences
    • Morningside Graduate School of Biomedical Sciences Dissertations and Theses
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of eScholarship@UMassChanCommunitiesPublication DateAuthorsUMass Chan AffiliationsTitlesDocument TypesKeywordsThis CollectionPublication DateAuthorsUMass Chan AffiliationsTitlesDocument TypesKeywords

    My Account

    LoginRegister

    Help

    AboutSubmission GuidelinesData Deposit PolicySearchingAccessibilityTerms of UseWebsite Migration FAQ

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    CD4 T Cell-Mediated Lysis and Polyclonal Activation of B Cells During Lymphocytic Choriomeningitis Virus Infection: A Dissertation

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Jellison_Evan.pdf
    Size:
    3.162Mb
    Format:
    PDF
    Download
    Authors
    Jellison, Evan Robert
    Faculty Advisor
    Raymond M. Welsh, Ph.D.
    Academic Program
    Immunology and Microbiology
    UMass Chan Affiliations
    Pathology
    Document Type
    Doctoral Dissertation
    Publication Date
    2008-01-10
    Keywords
    Cytotoxicity
    Immunologic
    Histocompatibility Antigens Class II
    Lymphocytic choriomeningitis virus
    Antigen Presentation
    B-Lymphocyte Subsets
    Lymphocyte Activation
    Receptors
    Antigen
    B-Cell
    Autoimmunity
    Biological Factors
    Cells
    Hemic and Immune Systems
    Viruses
    Show allShow less
    
    Metadata
    Show full item record
    Abstract
    CD4 T cells and B cells are cells associated with the adaptive immune system. The adaptive immune system is designed to mount a rapid antigen-specific response to pathogens by way of clonal expansions of T and B cells bearing discrete antigen-specific receptors. During viral infection, interactions between CD4 T cells and B cells occur in a dynamic process, where B cells that bind to the virus internalize and degrade virus particles. The B cells then present viral antigens to virus-specific CD4 T cells that activate the B cells and cause them to proliferate and differentiate into virus-specific antibody-secreting cells. Yet, non-specific hypergammaglobulinemia and the production of self-reactive antibodies occur during many viral infections, and studies have suggested that viral antigen-presenting B cells may become polyclonally activated by CD4 T cells in vivo in the absence of viral engagement of the B cell receptor. This presumed polyclonal B cell activation associated with virus infection is of great medical interest because it may be involved in the initiation of autoimmunity or contribute to the long-term maintenance of B cell memory. In order to directly examine the interactions that occur between T cells and B cells, I asked what would happen to a polyclonal population of B cells that are presenting viral antigens, if they were transferred into virus-infected hosts. I performed these studies in mice using the well-characterized lymphocytic choriomeningitis virus (LCMV) model of infection. I found that the transferred population of antigen-presenting B cells had two fates. Some antigen-expressing B cells were killed in vivo by CD4 T cells in the first day after transfer into LCMV-infected hosts. However, B cells that survived the cytotoxicity underwent a dynamic polyclonal activation manifested by proliferation, changes in phenotype, and antibody production. The specific elimination of antigen-presenting B cells following adoptive transfer into LCMV-infected hosts is the first evidence that MHC class II-restricted killing can occur in vivo during viral infection. This killing was specific, because only cells expressing specific viral peptides were eliminated, and they were only eliminated in LCMV-infected mice. In addition to peptide specificity, killing was restricted to MHC class II high cells that expressed the B cell markers B220 and CD19. Mice depleted of CD4 T cells prior to adoptive transfer did not eliminate virus-specific targets, suggesting that CD4 T cells are required for this killing. I found that CD4 T cell-dependent cytotoxicity cannot be solely explained by one mechanism, but Fas-FasL interactions and perforin are mechanisms used to induce lysis. Polyclonal B cell activation, hypothesized to be the cause of virus-induced hypergammaglobulinemia, has never been formally described in vivo. Based on previous studies of virus-induced hypergammaglobulinemia, which showed that CD4 T cells were required and that hypergammaglobulinemia was more likely to occur when virus grows to high titer in vivo, it was proposed that the B cells responsible for hypergammaglobulinemia may be expressing viral antigens to virus-specific CD4 T cells in vivo. CD4 T cells would then activate the B cells. However, because the antibodies produced during hypergammaglobulinemia are predominantly not virus-specific, nonvirus-specific B cells must be presenting viral antigens in vivo. In my studies, the adoptively transferred B cells that survived the MHC class II-restricted cytotoxicity became polyclonally activated in LCMV-infected mice. Most of the surviving naïve B cells presenting class II MHC peptides underwent an extensive differentiation process involving both proliferation and secretion of antibodies. Both events required CD4 cells and CD40/CD40L interactions to occur but B cell division did not require MyD88-dependent signaling, type I interferon signaling, or interferon γ signaling within B cells. No division or activation of B cells was detected at all in virus-infected hosts in the absence of cognate CD4 T cells and class II antigen. B cells taken from immunologically tolerant donor LCMV carrier mice with high LCMV antigen load became activated following adoptive transfer into LCMV-infected hosts, suggesting that B cells can present sufficient antigen for this process during a viral infection. A transgenic population of B cells presenting viral antigens was also stimulated to undergo polyclonal activation in LCMV-infected mice. Due to the high proportion of B cells stimulated by virus infection and the fact that transgenic B cells can be activated in this manner, I conclude that virus-induced polyclonal B cell activation is independent of B cell receptor specificity. This approach, therefore, formally demonstrates and quantifies a virus-induced polyclonal proliferation and differentiation of B cells which can occur in a B cell receptor-independent manner. By examining the fate of antigen-presenting B cells following adoptive transfer into LCMV-infected mice, I have been able to observe dynamic interactions between virus-specific CD4 T cells and B cells during viral infection. Adoptive transfer of antigen-presenting B cells results in CD4 T cell-mediated killing and polyclonal activation of B cells during LCMV infection. Studies showing requirements for CD4 T cells or MHC class II to control viral infections must now take MHC class II-restricted cytotoxicity into account. Polyclonal B cell activation after viral infection has the potential to enhance the maintenance of B cell memory or lead to the onset of autoimmune disease.
    DOI
    10.13028/4g3d-jc06
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/31667
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/4g3d-jc06
    Scopus Count
    Collections
    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Lamar Soutter Library, UMass Chan Medical School | 55 Lake Avenue North | Worcester, MA 01655 USA
    Quick Guide | escholarship@umassmed.edu
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.