Date of Award

1-1-2008

Degree Name

Doctor of Philosophy

Department

Molecular Biology, Microbiology and Biochemistry

First Advisor

Pauza, Mary

Abstract

T lymphocytes are necessary for an effective immune response; they protect us by destroying pathogens. Aside from their obvious importance in human health, the highly specialized and tightly controlled activities of T cells offer a unique test case for understanding cell regulation. This study is to investigate the mechanisms underlying c-Maf mediated control of developing and mature T cells. c-Maf, a basic leucine zipper transcription factor, is well known for its ability to promote T helper 2 (Th2) differentiation by direct transactivation of IL-4 following interaction with a consensus half MARE (Maf Response Element) site in the promoter. Although other c-Maf target genes are suggested by studies that demonstrate IL-4 independent changes occur in T cells that overexpress c-Maf, no specific genes have been identified yet. Studies presented here demonstrate that the function of c-Maf in T lineage cells can now be extended beyond transactivation of IL-4. Overexpression of c-Maf results in increased susceptibility of T cells to apoptosis induced by multiple stimuli, including growth factor withdrawal, dexamethasone, irradiation and T cell receptor (TCR) engagement. We also identified the mechanisms responsible for c-Maf regulation of apoptosis, which differ depending on the T cell lineage. In CD4 cells, c-Maf inhibits c-Myb binding to the Bcl-2 P2 promoter by interacting with c-Myb, which in turn disrupts Bcl-2 promoter activity. Downregulation of Bcl-2 expression limits CD4 cell survival following exposure to various stimuli. In CD8 cells, c-Maf transactivates Caspase 6 via binding to a consensus MARE site within the first intron. Upregulation of caspase 6 expression in c-Maf transgenic (Tg) cells provides increased substrate for caspase 6-dependent apoptosis pathways. In addition to influencing mature T cell survival, our studies show that c-Maf also regulates thymopoiesis. Largely independent of c-Myb and IL-4, overexpression of c-Maf influences thymocyte apoptosis, proliferation and emigration. Overall, c-Maf coordinates multiple processes including development and survival of T cells. Knowledge gained through these studies can be used to not only construct a more complete paradigm of c-Maf function in T cell immunity, but also evaluate c-Maf function as a predictive marker of autoimmune diseases.

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