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dc.contributor.authorBalasubrahmanyam, Priyanka
dc.date.accessioned2015-01-21T17:34:33Z
dc.date.available2015-01-21T17:34:33Z
dc.date.issued2014
dc.identifier.urihttp://hdl.handle.net/10713/4369
dc.descriptionUniversity of Maryland, Baltimore. Molecular Microbiology and Immunology. Ph.D. 2014en_US
dc.description.abstractNatural 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.en_US
dc.language.isoen_USen_US
dc.subjectBcl-xLen_US
dc.subject.lcshImmunologyen_US
dc.subject.meshAntigen Presentationen_US
dc.subject.meshAntigens, CD1den_US
dc.subject.meshLymphomaen_US
dc.subject.meshNatural Killer T-Cellsen_US
dc.titleThe Role of Natural Killer T Cells in B Cell Lymphomaen_US
dc.typedissertationen_US
dc.contributor.advisorWebb, Tonya J.
refterms.dateFOA2019-02-21T02:07:01Z


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