While studies have suggested that antigen presenting cells can strongly influence the nature of effector cell responses (e.g., Th1 versus Th2), our studies indicate unique differences exist between antigen presenting cells of different tissues with specific influences over CD4 T cell responses and inflammation. Moreover, the consequences of generating certain effector T cell phenotypes may vary from one tissue to the next. Thus, Th2 responses may be protective in autoimmune diabetes, yet pathogenic in lung responses to environmental antigen. The hypothesis to be tested in this proposal is that T cell responses to antigen are strongly influenced by tissue specific factors. Our focus will be on interactions between T cells and stromal cells in allergic lung inflammation, using a transgenic model of immunity against influenza hemagglutinin. While T cell derived cytokines influence types of inflammatory cell recruitment, these too are dependent on tissue specific factors. These studies should reveal mechanisms involved in lung inflammation, with possible application to asthma. 1. What is the role of alveolar macrophages versus airway dendritic cells in the stimulation of antigen specific T cell responses? Using T cell receptor transgenic mice specific for an influenza hemagglutinin peptide, we will study the immune responses generated to aerosol exposure to peptide, aggregated antigen, and infectious virus. Since susceptibility to allergic lung inflammation may be related to the time course of antigen exposure, we plan to test the possibility that perinatal exposure of mice to antigen will influence the adult immune response. These studies will be correlated with the ontogeny of various types of antigen presenting cells in the lung and expression of MHC class II and costimulatory molecules. 2. While Th1 and Th2 responses have been shown to have nearly antagonistic effects in tissues such as the pancreatic islet and central nervous system, they show at least one common feature; namely, a dominant lymphoid/mononuclear infiltrate. By contrast, both Th1 and Th2 responses in the lung appear to be dominated by granulocyte infiltrates. We intend to determine whether the recruitment of granulocytes is a direct result of chemokine produced by T cells, or by specific lung stromal cells (alveolar macrophages, lung alveolar epithelium, or fibroblasts). If, as we suspect, tissue stromal cells produce most of the specific chemokines, we will determine which factors are responsible for triggering them.
