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    Evaluation of IL2 and HLA on the Homeostasis and Function of Human CD4 and CD8 T Cells

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    Authors
    Durost, Philip A.
    Faculty Advisor
    Michael Brehm
    Academic Program
    Immunology and Microbiology
    UMass Chan Affiliations
    Molecular Medicine
    Document Type
    Doctoral Dissertation
    Publication Date
    2017-09-15
    Keywords
    IL-2
    HLA
    Treg
    T cell
    CD4
    CD8
    GVHD
    AAV8
    gene therapy
    Immunity
    
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    Abstract
    Homeostasis of human T cells is regulated by many factors that control proliferation, differentiation of effector cells and generation of memory. Our current knowledge of the mechanisms controlling human T cell homeostasis in vivo is based on experiments in small animal models. However many differences exist between immune systems of mice and humans, including cell composition, function, and gene expression. Humanized mouse models have shown great value in the study of human immunobiology. I have used novel humanized mouse models to examine the role of human MHC (HLA) and human IL2 in CD8 T cell and CD4 regulatory T cell (Treg) homeostasis. To study human CD8 T cells I engrafted CD8 T cells from healthy donor PBMC into NOD-scid IL2rgnull (NSG) mice that lacked expression of murine MHC and that expressed HLA-A2. My data demonstrate that CD8 T cell survival and effector function required the presence of HLA-A2, helper function from human CD4 T cells and exogenous human IL2. To study human Treg homeostasis I used NSG mice engrafted with human fetal thymus and hematopoietic stem cells (BLT model). NSG-BLT mice support the growth of human thymic tissue and enable the efficient development of HLA-restricted Treg and conventional T cells. Using an AAV vector to express human IL2, I demonstrated that functional human Treg but not conventional T cells increased in number in NSG-BLT mice and that this coincided with increases in activated human NK cells. Overall my research has revealed that HLA and human IL2 have an essential role in human T cell survival and function in vivo.
    DOI
    10.13028/M2C979
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32319
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M2C979
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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