Student Theses and Dissertations

Randy Longman

Date of Award

2006

Document Type

Thesis

RU Laboratory

Rice Laboratory

Keywords

hepatitis C virus, HCV immunity, interferon alpha/beta, conventional dendritic cells

Abstract

Hepatitis C virus (HCV) infects an estimated 170 million people and is responsible for considerable morbidity and mortality worldwide. Successful resolution of infection is achieved naturally in approximately 30% of infected individuals and correlates with a strong T cell response. Furthermore, treatment with interferon (IFN)a achieves sustained virologic response in approximately 50% of chronically infected individuals. Conventional dendritic cells (cDCs), as the most potent antigen presenting cells, and plasmacytoid DCs (pDCs), as the principal IFNa/|3 producing cells, serve as potential targets for both immune evasion and therapeutic strategies. In order to evaluate the effects of HCV on DC function, we compared phenotypic and functional characteristics of DCs from chronically infected patients to DCs from healthy donors. Our results suggest that despite non-specific decreases in total numbers, DC phenotypic and functional integrity is maintained. Consequently, we propose that other factors associated with HCV immunity may act on DCs to regulate pathogenesis and immunity. In light of the important roles of IFNa/p and CD4+ T cells in the clinical response to HCV, we focused on the interplay of these factors with DCs during CD8+ T cell priming. Using a human in vitro cross-presentation system, we found that IFNa/p acts on immature DCs (iDCs) to inhibit CD8+ T cell activation by cross-presentation. Further analysis revealed that ST ATIdependent inhibition of CD40-induced IL-12 was responsible for this block. In contrast, a switch from STAT1 to STAT4 signaling enabled an immune enhancing effect of IFNa/p on mature DCs (mDCs) that potentiated CD8+ T cell activation. In order to evaluate this latter effect in vivo, we monitored the ability of pDC IFNa/p production to substitute for CD4+ T cells in CD8+ T cell priming. The results revealed that pDC activation overcomes the need for CD4 'help' in priming CD8+ T cell responses in an IFNa/p receptor-dependent manner. Importantly, IFNa/p produced by non-pDCs did not provide similar priming signals. These results provide support for HCV immunotherapy trials and offer a unique mechanism to account for the dual effects of IFNa/p in pathogenesis and immunity.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Permanent URL

http://hdl.handle.net/10209/230

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