All ETDs from UAB

Advisory Committee Chair

Paul A Goepfert

Advisory Committee Members

David D Chaplin

Laurie E Harrington

Zdenek Hel

Jan Novak

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

CD8 T cells play a critical role in controlling intracellular pathogens, particularly viruses. However, during persistent viral infections, such as human immunodeficiency virus-1 (HIV-1) infection, virus-specific CD8 T cells become increasingly impaired by poorly understood mechanisms. Massive CD4 T cell depletion is a hallmark of HIV-1 infection and is associated with CD8 T cell dysfunction and ineffective viral containment. CD4 T cells provide critical helper signals to CD8 T cells, especially during uncontrolled viral infections. Mouse models of chronic viral infection implicate interleukin-21 (IL-21), produced primarily by CD4 T cells, as a vital factor necessary for the maintenance of fully functional CD8 T cells and viral containment. The studies presented in this dissertation have investigated the role of IL-21 as a mediator of CD4 T cell help during HIV-1 infection. Our results demonstrate that both CD4 and CD8 T cells produce IL-21 in response HIV-1, with the latter cell type more closely associated with viral control. IL-21-producing CD4 T cells, compared to those producing other cytokines, were the best indicator of functional CD8 T cells. Interestingly, virus-specific CD8 T cells were not identified outside the context of HIV-1 infection. We therefore hypothesized that under conditions of reduced CD4 T cell help, as seen in HIV-1 infection, CD8 T cells producing IL-21 may partially compensate for this loss. Upon polyclonal stimulation, IL-21-producing CD8 T cells exhibited some characteristics of helper T cells, including impaired production of perforin and granzyme B as well as CD40 ligand upregulation; however, we observed limited expression of the chemokine receptor CXCR5, suggesting a functional profile distinct from the T follicular helper subset. Our studies reveal that CD8 T cell induction of IL-21 competency is independent of CD4 T cell loss but instead contingent upon the extent of peripheral CD8 T cell activation. These findings suggest that IL-21 production is remarkably limited to CD4 T cells during the steady state, and CD8 T cells producing IL-21 can either mediate viral control or moderate inflammation depending on whether these cells act in a specific or nonspecific manner, respectively.

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