Date of Award

2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Immunology

First Advisor

Andrew Wells

Abstract

Naive CD8+ T cells represent one of the most potent cells in immunity, as they can differentiate into cytolytic T lymphocytes (CTLs) that lyses virally infected cells or tumor cells through the production of IFN-g, TNF-a, Perforin and Granzyme B. Their ability to differentiate into highly potent CTLs needs to be a tightly regulated process in order to prevent autoimmunity and disease. However, activation in the absence of key support such as cytokine signals or CD4+ T cell help, or constant challenge with antigen can result in hyporesponsiveness of CD8+ T cells and their failure to mount a robust immune response. Interest has grown in studying the epigenetics of T cells, as chromatin accessibility of key cytokine and lytic mediator loci can determine the ability of the T cell to respond to antigen. Identifying the transcriptional regulators of naive CD8+ T cell differentiation and activation is key to learning how to modulate the CD8+ T cell response. Ikaros is a chromatin-remodeling factor that has been identified to regulate autocrine IL-2 production by and the differentiation program of CD4+ T cells in response to TCR and CD28 signals. As CD8+ T cells make little IL-2 and are dependent on paracrine IL-2 or inflammatory signals for their differentiation, we hypothesized that Ikaros could regulate naïve CD8+ T cell differentiation through restriction of autocrine IL-2 production. In this thesis, I demonstrate that naïve CD8+ T cells with only one copy of Ikaros can differentiate in vitro into cytolytic effectors with enhanced effector function, and this results from increased autocrine IL-2 production. This enhanced effector function also sparked an investigation into pre-clinical models of cellular immunotherapy for cancer, to determine if the Ikzf1+/- CTLs had enhanced anti-tumor function. In conclusion, modulating Ikaros activity represents a new approach to controlling naïve CD8+ T cell differentiation and effector function. Through being able to produce more autocrine IL-2, an Ikzf1+/- CD8+ T cell may not require paracrine IL-2 from CD4+ T cells and can possibly resist the "exhausted" CD8+ T cell effector state during chronic antigen exposure. Thus, investigating Ikaros' role in CD8+ T cell biology will help to elucidate how this chromatin remodeling factor can influence appropriate CD8+ T cells responses to self and foreign antigen, and ensure against inappropriate immunopathology caused by activated CD8+ T cells.

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