All ETDs from UAB

Advisory Committee Chair

Allan J Zajac

Advisory Committee Members

Paul A Goepfert

Louis B Justement

Casey D Morrow

John D Mountz

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

CD8 T cells contribute to the control of intracellular pathogens including viruses and certain bacteria. Recognition of foreign antigens by antigen-specific CD8 T cells initiates a differentiation process by which CD8 T cells gain effector functions including the ability to rapidly produce cytokines and kill infected cells. Currently, it is not well understood what signals dictate the generation of robust CD8 T cell responses, however it has been demonstrated that without CD4 T cell help CD8 T cell responses are compromised. CD4 T cells are the primary producers of interleukin-21 (IL-21), which has broad immunological actions. Thus for this dissertation, I have investigated the roles of IL-21 in regulating the phenotypic and functional attributes of CD8 T cell responses using well-established murine models of acute and chronic viral infections. Our results show that during a chronic infection the consequences of insufficient levels of IL-21 are catastrophic, resulting in severe functional exhaustion and the establishment of a persistent infection. Interestingly, many of the phenotypic and functional impairments of CD8 T cell responses, which manifested in the absence of IL-21, resemble the defects observed in CD4 T cell deficient hosts. Using mixed bone marrow chimera studies we show that CD8 T cells that are unable to receive IL-21 signals are unable to compete and persist with CD8 T cells that are able to receive IL-21 signals during a chronic infection; demonstrating a direct effect of IL-21 in promoting the functional quality of CD8 T cell responses. Significantly, IL-21 treatment in chronically infected CD4-/- mice prevented the onset of T cell exhaustion and reduced viral loads. Although the phenotype in IL-21 deficient mice during an acute infection is not as dramatic as in a chronic infection, we observe a diminution in the generation of polyfunctional CD8 T cells which is distinguished by the ability to produce IL-2. Therefore, IL-21 serves as a critical factor that helps CD8 T cell responses especially during chronic infections. These findings advance our understanding of how CD8 T cell responses to persistent antigens are regulated and may have practical implications for enhancing immunity to chronic infections.

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