Date of Degree
PhD (Doctor of Philosophy)
Steven M. Varga
The respiratory system forms a major mucosal interface with the external environment. Consequently, the respiratory tract is constantly exposed to inhaled foreign antigens, commensal microorganisms, and potential pathogens. The respiratory system has evolved a complex regulatory network designed to prevent unnecessary inflammation to harmless antigens and to limit immune-mediated damage to the fragile lung epithelium in response to infection. The lung maintains a default anti-inflammatory state that is coordinated by the respiratory epithelium, alveolar macrophages, dendritic cells, and regulatory Foxp3+ CD4 T cells (Tregs). It is likely that all of these cells influence the development of pathogen-specific T cell responses in the lung. Following infection with a respiratory virus, virus-specific CD8 T cells in the lung are inhibited in their ability to produce cytokines. Current studies suggest that this functional inactivation occurs following infection with respiratory viruses within the Paramyxoviridae family. The data presented here demonstrate that suppression of effector functions of virus-specific CD8 T cells in the lungs occurs following infection with several unrelated respiratory viruses. These results indicate that the functional inhibition of virus-specific T cell responses is not restricted to infection with viruses from the Paramyxoviridae family. Furthermore, I show data indicating that the functional inactivation of virus-specific CD8 T cells in the lungs occurs in the absence of infection. I also demonstrate for the first time that the lung environment also regulates the effector functions of virus-specific CD4 T cells. Inhibition of cytokine production by pulmonary T cells is reversible as stimulation with exogenous peptide-pulsed antigen-presenting cells rescues IFN-gamma production. The inhibition of IFN-gamma production by virus-specific T cells occurs in other organs such as the kidney. These data suggest that regulation of T cell cytokine production by peripheral tissues may serve as an important mechanism to prevent immunopathology and preserve normal tissue function.
Foxp3+ Tregs have been shown to inhibit conventional effector T cell responses in a large number of chronic infection models. However, their role during acute infections remains unclear. Examination of Foxp3+ Tregs during RSV infection showed that Tregs are rapidly recruited into the lungs and acquire an activated phenotype. Depletion of Foxp3+ Tregs prior to RSV infection revealed that Tregs facilitate the early recruitment of RSV-specific CD8 T cells from the draining lymph nodes to the lung and later limit the overall magnitude of the virus-specific CD8 T cell response. Depletion of Tregs increased TNF-αa production by RSV-specific CD8 T cells and enhanced T-cell-mediated immunopathology. These data demonstrate that Foxp3+ Tregs play a major role in regulating CD8 T cell responses to respiratory virus infections. Collectively, the data presented here demonstrate that CD8 T cell responses to respiratory pathogens are tightly regulated within the lung environment.
lung, mouse, regulation, T cell, virus
xii, 176 pages
Includes bibliographical references (pages 158-176).
Copyright 2010 Ross Fulton