Document Type

Dissertation

Date of Degree

Spring 2014

Degree Name

PhD (Doctor of Philosophy)

Degree In

Immunology

First Advisor

Steven M. Varga

Abstract

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in young children. RSV induces variable disease severities in infected children. Severe cases of RSV-induced disease result in bronchiolitis, with a subset of children going onto develop long-term airway morbidities. The host antiviral T cell response is believed to contribute to the severity of pulmonary disease following acute RSV infection. However recent work has questioned the relative proportion of T cells that migrate into the lung tissue following a respiratory virus infection. Using in vivo intravascular antibody labeling, >80% of antigen-specific effector T cells were found to remain in the pulmonary vasculature following an intratracheal infection with the systemic viral pathogen lymphocytic choriomeningitis virus (LCMV). Therefore, I determined the proportion of RSV-specific CD4 T cells located within the lung tissue following infection. In contrast to recent reports with LCMV-specific CD8 T cells, I found approximately 85% of RSV-specific CD4 T cells were located within the lung tissue, indicating that the vast majority of virus-specific effector CD4 T cells are located within the lung tissue and not in the pulmonary vasculature following an acute RSV infection.

Genetic variations can occur in the circulating RSV strains both within and between infectious seasons. Therefore, I questioned if different RSV strains could induce differential CD4 T cell responses. I demonstrate that RSV strains induce differential CD4 T helper responses, which are associated with the differential activation of the innate immune response. The RSV line 19 strain induced the early production of the pro-inflammatory cytokines IL-1Β and IL-6 resulting in an increased Th17 response as compared to the RSV strains A2 and 2-20. Blockade and/or neutralization of IL-1Β and IL-6 inhibited the ability of RSV line 19 to induce a Th17 response. These results demonstrate that RSV strains can differentially activate innate immunity that subsequently influences the type of adaptive immune response. This in part may contribute to differential RSV pathogenesis and the development of long-term airway morbidities observed in humans.

IL-10 is a pleotropic cytokine able to suppress the adaptive immune response. Because the host adaptive immune response is believed to contribute to RSV-induced pulmonary disease, I evaluated the role of IL-10 in modulating the RSV-specific immune response. I found that IL-10 protein levels in the lung were increased following acute RSV infection with maximum production corresponding to the peak of the virus-specific T cell response. Multiple populations of CD4 T cells accounted for the majority of IL-10 produced in the lung including Foxp3+ Tregs, Foxp3- CD4 T cells that co-produce IFN-Γ, and Foxp3- CD4 T cells that do not co-produce IFN-Γ. Furthermore, RSV-induced disease severity was increased in both the absence of IL-10 and following IL-10 receptor blockade as compared to control mice. I also observed an increase in the magnitude of the RSV-induced CD8 and CD4 T cell response that correlated with increased disease severity following IL-10 receptor blockade. IL-10 receptor blockade during acute RSV infection altered CD4 T cell subset distribution, resulting in a significant increase in IL-17A-producing CD4 T cells and a concomitant decrease in Foxp3+ regulatory T cells. These results demonstrate that IL-10 plays a critical role in modulating the adaptive immune response to RSV by limiting T-cell-mediated pulmonary inflammation and injury. Overall, my data demonstrate that RSV-specific CD4 T cells migrate into the lung tissue with their differentiation influenced by the strain-specific activation of innate immune response. IL-10 is then produced by CD4 T cells to regulate the RSV-specific T cell responses and inhibit virus-induced immunopathology. My data indicate that there are multiple targets for immunotherapy for individuals with severe RSV-induced disease.

Keywords

Cytokine, T cells, Virus

Pages

xiii, 166 pages

Bibliography

Includes bibliographical references (pages 142-166).

Comments

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Copyright

Copyright 2014 Kayla Ann Weiss

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