Examining dioxin-mediated alterations in pulmonary immune cell function during influenza virus infection : effects on cytolytic activity and interferon gamma

by Neff-Laford, Haley D.

By Haley Neff-LaFord, Ph.D. Washington State University May 2006 Chair: B. Paige Lawrence 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent immunotoxicant with the highest binding affinity for a transcriptional regulator known as the aryl hydrocarbon receptor (AhR). Using a murine influenza virus model, we have shown that mice treated with TCDD die from an otherwise non-lethal infection, and have fewer cytotoxic T lymphocytes (CTL) in their lungs. This reduction in the number of CTL is critical because CTL are the principal cells responsible for eliminating virus in a primary infection. In spite of fewer CTL, TCDD-treated mice that survive infection successfully eliminate the virus. We hypothesized that a non-CTL-mediated mechanism was responsible for killing the virus-infected cells in the lung. However, we found that exposure to TCDD did not increase anti-viral cytokine levels or NK cell activity in the lung during infection. Instead, we found that the CTL, although fewer in number, are sufficient for viral clearance from the lungs of immunocompromised mice. viii In addition to decreasing the CTL response, exposure to TCDD elevates pulmonary interferon gamma (IFN?) levels. This is of interest because while some level of IFN? is important for anti-viral immunity, excessive IFN? production is associated with enhanced inflammation and tissue damage. We found that influenza virus infection stimulates IFN? production by multiple immune cell types. Interestingly, the majority of the IFN? in the lungs of both vehicle- and TCDD-treated mice is produced by phagocytic cells, a non-typical source of IFN?. The elevated IFN? production correlates with an increase in inducible nitric oxide synthase (iNOS) levels in the lungs of TCDD-treated mice. Using CD45.2AhR-/-? CD45.1AhR+/+ bone marrow chimeric mice we found that AhR-driven events external to the immune system mediate the exacerbated levels of IFN? and iNOS during infection. Furthermore, we found that a novel iNOS-mediated mechanism may be responsible for the elevated IFN? levels in the lung. Given that chronic inflammatory diseases of the lower respiratory tract are on the rise worldwide, and that high levels of both IFN? and iNOS have been associated with the pathology of these diseases, our data suggest that environmental exposure to AhR ligands may contribute to the development of these disorders. ix