Regulation of Pulmonary Cytotoxic T Lymphocyte Immune Response to Influenza Infection

Author:
Hufford, Matthew T., Department of Microbiology, University of Virginia
Advisors:
Braciale, Thomas, Department of Microbiology, University of Virginia
Bender, Timothy, Department of Microbiology, University of Virginia
Erickson, Loren, Department of Microbiology, University of Virginia
Hahn, Young, Department of Microbiology, University of Virginia
Mehrad, Borna, Department of Medicine, University of Virginia
White, Judy, Department of Cell Biology, University of Virginia
Abstract:

CD8 + T cells (cytotoxic T lymphocytes) are critical in a number of respiratory viral infections via their ability to release pro-inflammatory cytokines and to initiate targeted cell death (i.e. cytotoxicity). The stimulation of these anti-viral activities must not only be robust enough to achieve viral clearance but also regulated to minimize tissue damage. The factors controlling these effector activities at infection sites in vivo, though, are poorly understood. Utilizing a murine model of influenza infection, we observed that the expression of CD8 + T cell anti-viral activity in the infected respiratory tract was dictated by the target cell encountered. Non-hematopoietic cells, including the influenza-infected respiratory epithelium, stimulated only CD8 + T cell cytotoxicity, which was sufficient in itself to achieve CD8 + T cell mediated influenza viral clearance within the respiratory tract. In contrast, hematopoietic cells triggered CD8 + T cell cytotoxicity, cellular proliferation, and the release of pro-inflammatory cytokines (e.g. IFN). We further demonstrated that two distinct hematopoietic subsets trigger CD8 + T cell anti-viral activity. Inflammatory mononuclear cells, the prominent antigen-bearing population within the influenza-infected lung, stimulated influenza-specific CD8 + T cell cytokine production in vivo. Neutrophils, whether infected with influenza virus or cross-presenting influenza antigen, triggered CD8 + T cell proliferation and cytokine production in vitro and in vivo. Furthermore, CD8 + T cell mediated cytotoxicity was dependent on MHC Class I expression while CD8 + T cell cytokine production required additional signaling, such as co-stimulation (e.g. CD80 and CD86). The expression of these co-stimulatory molecules was restricted to cells of hematopoietic origin in vivo and may, in part, reflect the ability of these cells to trigger CD8 + T cell cytokine production. Importantly, acute iii antibody blockade of co-stimulation in vivo at the time of effector CD8 + T cell migration into the infected lung, reduced CD8 + T cell derived pro-inflammatory cytokines but had no impact on cytotoxic clearance of the virally infected respiratory epithelium. These findings suggest that the quality of CD8 + T cell effector activity is dependent on a signal hierarchy in vivo, which is potentially important in controlling excess pulmonary inflammation while preserving optimal viral clearance during respiratory virus infections.

Note: Abstract extracted from PDF text

Degree:
PHD (Doctor of Philosophy)
Language:
English
Rights:
All rights reserved (no additional license for public reuse)
Issued Date:
2011/12/01