Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) suppresses the humoral and cell-mediated immune responses to influenza A virus without affecting cytolytic activity in the lung

The immune response to influenza virus is exquisitely sensitive to suppress ion by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); however er, the cellular mechanisms underlying the suppressive effects of TCDD are unknown. Mice ex posed to TCDD exhibited a dose-responsive increase in mortality following a n otherwise non-lethal influenza virus infection. Given that cytotoxic T ly mphocytes (CTL) an generally thought to resolve primary infections in the l ung, we tested the hypothesis that exposure to TCDD suppresses T-cell respo nsiveness , leading to decreased CTL in the lung. After infection with infl uenza virus, naive CD8(+) lymphocytes are activated and differentiate in th e mediastinal IJ;mph node (MLN). Ln mice exposed to TCDD and infected with influenza virus, the number of CD8(+) MLN cells was reduced 60% compared to vehicle-treated mice. Moreover, MLN cells from TCDD-treated mice failed to develop cytolytic activity, and the production of interleukin (IL)-2 and i nterferon (IFN)-gamma was suppressed. Exposure to TCDD also altered the pro duction of virus-specific antibodies, decreased the recruitment of CD8(+) c ells to the lung, reduced the percentage and number of bronchoalveolar lava ge cells bearing a CTL phenotype (CD8(+)CD44(hi)CD62(lo)), and suppressed I L-12 levels in the lung. Despite our findings that exposure to TCDD suppres sed T cell-dependent functions, the cytolytic activity of lung lavage cells from TCDD and vehicle treated mice was equivalent, and IFN gamma levels in the lungs of mice treated with TCDD were enhanced 10-fold. Thus, while exp osure to TCDD suppressed a number of responses associated with the developm ent of adaptive immunity to influenza virus, a direct link between these ef fects and enhanced susceptibility to influenza remains unclear.