Dendritic Cells Mediate the Dual Effects of IFN alpha/beta in HCV Immunity

<p>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)α 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 IFNα/β 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 IFNα/β 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 IFNα/β acts on immature DCs (iDCs) to inhibit CD8+ T cell activation by cross-presentation. Further analysis revealed that STAT1-dependent 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 IFNα/β 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 IFNα/β 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 IFNα/β receptor-dependent manner. Importantly, IFNα/β 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 IFNα/β in pathogenesis and immunity.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year

2006

Author dc:creator

• Longman, Randy

Contributors dc:contributor

• Charles M. Rice

• hepatitis C virus (HCV)
• HCV immunity
• interferon alpha/beta
• dendritic cells
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/54

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1053