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    • Albert Einstein College of Medicine: Doctoral Dissertations
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    • Albert Einstein College of Medicine (AECOM)
    • Albert Einstein College of Medicine: Doctoral Dissertations
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    A study of pathogenic CD8+ T cells in autoimmune diabetes

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    Date
    2005
    Author
    Lieberman, Scott Matthew
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    Abstract
    Nonobese diabetic (NOD) mice develop an autoimmune disease that models human type 1 diabetes. CD8+ T cells are required for the development of the beta cell destruction characteristic of autoimmune diabetes, yet their specific antigenic targets are largely unknown. We have studied two diabetogenic CD8+ T cell clones, 8.3 and AI4, representing CD8+ T cell clonotypes present within the earliest islet infiltrates of NOD mice and whose antigenic targets are unknown. We screened peptides eluted from immunoaffinity purified MHC molecules from an NOD-derived beta cell line (NIT-1) and identified islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) as the antigenic target of the prevalent and pathogenic 8.3-like T cell population. To characterize AI4-like T cells, we screened a combinatorial peptide library and identified a mimotope peptide recognized by AI4. We used mimotope peptide/MHC tetramers to demonstrate that AI4-like T cells are detectable in islet infiltrates of NOD mice. We then identified a mimotope-like peptide, contained within a ubiquitously expressed protein (dystrophia myotonica kinase; DMK), that is recognized by AI4. We cloned DMK from NIT-1 beta cells and demonstrated AI4 recognition of DMK-transfected target cells. Identification of target autoantigens is a key step in understanding the mechanisms responsible for the defect in establishing and/or maintaining tolerance to certain self proteins. Knowledge of the antigenic targets of the pathogenic 8.3- and AI4-like T cells will allow for studies into the development of these autoreactive T cell populations in NOD mice as well as the importance of these autoantigens in human type 1 diabetes.
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    https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3142198
    https://hdl.handle.net/20.500.12202/732
    Citation
    Source: Dissertation Abstracts International, Volume: 65-09, Section: B, page: 4498.;Advisors: Teresa P. DiLorenzo.
    *This is constructed from limited available data and may be imprecise.
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