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    The Role of Natural Killer T Cells in B Cell Lymphoma

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    Author
    Balasubrahmanyam, Priyanka
    Advisor
    Webb, Tonya J.
    Date
    2014
    Type
    dissertation
    
    Metadata
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    Abstract
    Natural killer T (NKT) cells are a unique subset of T cells that recognize glycolipid antigens in the context of CD1d, a non-classical MHC class I-like molecule. NKT cells mount strong anti-tumor responses and are a major focus in developing effective cancer immunotherapy. However, little is known about the regulation of CD1d-mediated antigen presentation to NKT cells, particularly in the context of B cell lymphoma. Pro-survival factors of the Bcl-2 family, such as Bcl-xL are often upregulated in B cell lymphomas, and are associated with changes in the endocytic pathway, which is paramount for CD1d-mediated antigen presentation. We hypothesized that Bcl-xL can regulate this process, and found that over-expression or induction of Bcl-xL led to increased CD1d-mediated antigen presentation to NKT cells. Conversely, pharmacological inhibition or shRNA-mediated knockdown of Bcl-xL led to decreased antigen presentation. Surface CD1d expression was unchanged by the modulation of Bcl-xL, but its knockdown resulted in reduced CD1d trafficking to LAMP1+ compartments. Furthermore, Rab7, a late endosomal marker was upregulated following Bcl-xL knockdown, and CD1d molecules accumulated in the late endosomes. These results demonstrate that Bcl-xL modulates CD1d-mediated antigen presentation to NKT cells by altering the intracellular trafficking of CD1d. Thus, we have identified a potential tumor recognition mechanism that can impact current therapies targeting the Bcl-2 family, as well as emerging NKT cell based cancer immunotherapeutic strategies. We further studied the role of NKT cells in mantle cell lymphoma, a particularly aggressive form of non-Hodgkin's lymphoma, in vivo, using an IL-14α and c-Myc double-transgenic mouse model. We found that treatment with a single dose of the NKT cell agonist α-Galactosylceramide, increased survival and caused amelioration of disease. Ex vivo restimulation of splenocytes with α-GalCer showed increased IFN-γ responses, providing some insight into the mechanism underlying the enhanced anti-tumor response following α-GalCer administration. These studies indicate that NKT cells play an important role in mediating an effective immune response to lymphoma, warranting further investigation of the CD1d/NKT system. This small but powerful lymphocyte population bears high potential for translation into the next generation of cancer therapy.
    Description
    University of Maryland, Baltimore. Molecular Microbiology and Immunology. Ph.D. 2014
    Keyword
    Bcl-xL
    Immunology
    Antigen Presentation
    Antigens, CD1d
    Lymphoma
    Natural Killer T-Cells
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/4369
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