Date of Completion

6-2-2014

Embargo Period

5-27-2015

Keywords

Pregnane X receptor, Inflammation, Mibrobial infection, Cytomegalovirus, CD8+ T cell response, melanoma, vaccine

Major Advisor

Kamal M. Khanna

Associate Advisor

Lynn Puddington

Associate Advisor

Adam Adler

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Campus Access

Abstract

The pregnane X receptor (PXR), also known as steroid and xenobiotic receptor, pregnane activated receptor or NR1l2, is a nuclear receptor that is highly expressed in the intestine and liver and plays a critical role in regulating xenobiotic metabolisom. Recent studies have suggested that PXR cross talks with NF-κB signaling pathway in intestinal epithelial cells and hepatocytes and therefore regulates inflammation in the intestine and liver. However, its role in the immune system is not known. In Chapter III, We defined a novel hematopoietic intrinsic role for PXR as a critical regulator of pathogen-induced inflammation and host defense against microbial infection by modulating the toll-like receptor 4 (TLR4) signaling pathway. Our study suggests that PXR can be a novel pharmaceutical target for inflammatory diseases.

CD8+ T cells are effective for tumor rejection. The presence of tumor infiltrating CD8+ T cells is associated with tumor regression and better prognosis. Cytomegalovirus (CMV) infection elicits a robust and long-lasting CD8+ T cell response, which makes CMV a potentially promising vaccine vector against cancer. In Chapter IV, we constructed a CMV-based cancer vaccine by engineering CMV to express a modified tumor antigen. We demonstrated that immunization with this vaccine was effective in overcoming the immune suppressive environment and the immune tolerance to tumor antigens and induced robust antitumoral CD8+ T cells, which resulted in subsequent tumor regression. Our study suggests that CMV is a promising vaccine vector to prevent and treat cancers.

CMV is an opportunistic pathogen that can cause serious diseases in individuals with an immature or compromised immune system. CMV infection induces potent CD8+ T cell responses that increase with age, a phenomenon called “memory inflation”. These CD8+ T cells are central to controlling viral reactivation. In Chapter V, we demonstrated that antigens were constantly presented to CD8+ T cells, which likely drove the inflationary CD8+ T cell response. The inflationary CD8+ T cell pool sustained without the replenishment of naïve T cells. Furthermore, these inflationary CD8+ T cells expressed few inhibitory molecules and maintained polyfunctional during latency. Our study has important implications for the development of T cell based anti-CMV vaccines.

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