Dendritic cell immunobiology and pulmonary immunity
My laboratory is focused upon determining the role that respiratory dendritic cells (rDC) play in initiating and regulating the T cell responses to pulmonary pathogens, in particular influenza virus (IAV). We have shown that IAV infections trigger a rapid but transient migration of mature rDC from the lungs to the lymph nodes. This halt in rDC migration results in a suppression of pulmonary T cell responses to subsequent infections and therefore may contribute to the high preponderance of secondary bacterial pneumonias that occur following respiratory virus infections. However the retention of the DC in the lungs also importantly allows local peripheral interactions of the DC with effector T cells - therein boosting pulmonary CD8 T cell responses and allowing viral clearance and recovery from infection.
The laboratory is also focused on delineating the factors that control rDC programming in the lungs and how the type and degree of the pulmonary infection is translated by rDC into different effector programming of T cells within the lymph nodes. Our work has shown that the degree of IAV infection leads to diverse programming of rDC, which in turn results in differential DC cytokine production in the lymph nodes and distinct levels of T cell fitness.
Additional studies are determining how chronic alcohol consumption increases the severity of pulmonary infections. Alcoholics are known to be at increased risk for severe pulmonary infections, yet the underlying changes in immunity that correspond with the increased disease are poorly understood. Our current work suggests that alterations in CD8 T cell responses, neutrophilia, edema, and DC all contribute to the increased severity. Further we have shown that exposure to ethanol during fetal development leads to long-term increases in susceptibility to IAV and group A Streptococcus infections.
Overall the goals of our studies are to determine which DC-derived factors and interactions are necessary to induce protective T cell responses during pathogen infections of the lungs. This knowledge will be important in the rational design of methods to alter respiratory immunopathology, improve vaccinations, and boost T cell responses to influenza virus and other pulmonary pathogens.