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dc.contributor.authorAbe, Brian Tadayoshi
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 73-07(E), Section: B.;Advisors: Fernando Macian-Juan.
dc.description.abstractTumor recognition and elimination by the immune system is key to limiting cancer development. The T cell arm of the adaptive immune system has the potential for detecting and removing transformed cells expressing neo-antigens, however cancer cells have been shown to evade the immune system by inducing tolerance particularly in the CD4+ T helper cell compartment.;CD4+ T cells are properly activated by signaling through the antigen-specific T cell receptor (TCR) and co-stimulatory receptors. In the absence of co-stimulatory receptor engagement, suboptimally activated T cells enter a state of anergy and become unresponsive to subsequent proper stimulations. The TCR-activated, calcineurin-dependent transcription factor NFAT1 forms homodimers in the nucleus of T cells receiving anergizing stimuli and induces the expression of anergic genes, including Grail and Casp3 that are essential to maintain the T cell in this tolerized state. We therefore hypothesized that tumors induce tolerance in CD4+ T cells through an NFAT1-dependent mechanism, allowing tumor-induced immunosuppression and escape from immune surveillance. We observed tumor-induced CD4+ T cell anergy in tumor-infiltrating T cells and draining lymph nodes of OT-II TCR-transgenic mice challenged with B16-OVA melanoma. These T cells showed defects in IL-2 and IFN-gamma production and proliferation, and up-regulated the expression of Grail. Supporting the role of NFAT1-regulated programs of T cell tolerance in the context of tumor immune escape, Nfat1-/- OT-II mice showed increased resistance to tumor growth when challenged with B16-OVA melanoma compared to wildtype controls in a CD4+ T cell specific manner. Additionally, CD4+ T cells from these mice produced IL-2 and IFN-gamma, and did not up-regulate anergy associated genes.;Our results also showed that tumor specific cells produced less IL-17A compared to controls suggesting possible tumor-induced Th17 cell anergy. Furthermore, in vitro anergized Th17 cells up-regulated anergic genes and were hypo-responsive upon full stimulation.;As NFAT1 homodimers are involved in the expression of several anergic genes, we synthesized peptides that inhibit NFAT1 homodimers. These inhibitors decreased Grail expression and increased proliferation in re-stimulated T cells previously anergized in vitro. These results pave a new therapeutic avenue targeting NFAT1 homodimers to augment T cell responses in tumor immunity.
dc.publisherProQuest Dissertations & Theses
dc.titleThe role of NFAT1 in tumor-induced CD4+ T cell tolerance

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