Initiation of Immune Responses by Dendritic Cells
Our laboratory is interested in understanding the cellular and molecular basis of T cell priming by dendritic cells (DCs) in diseases such as type 1 diabetes and pancreatic cancer. Adaptive immune responses begin with the stimulation of naive T cells and the subsequent generation of effector T cells, a process generically referred to as priming. T cells do not recognize antigens in their native state but rather respond to MHC-peptide complexes on the plasma membrane of an antigen-presenting cell. Because naive T cells home to specific regions of secondary lymphoid organs that are impenetrable by most free antigens, epitopes for which they are specific must be delivered to T cell zones of secondary lymphoid tissues and presented there by professional antigen-presenting cells. DCs, the most potent of all antigen-presenting cells, are essential players at every step of this process.A major focus of our research is the impact of healthy and inflamed tissue microenvironments on the development, differentiation, and function of DCs. In particular, we strive to understand how perturbations to the tissue microenvironment affect the presentation of self-antigens by DCs. We combine transgenic mouse models and high-resolution imaging technologies to explore endocytosis, transport, and processing of tissue-restricted antigens by DCs. We recently developed two mouse models in which specific mutations in the NF-kappa B pathway and new variants of fluorescent proteins are targeted selectively to DCs. We have also initiated studies to discover novel genes that regulate the internalization and processing of self-antigens by DCs. Ultimately, elucidating the steps leading to primary immune responses against self-antigens should provide the necessary framework for enhancing this process in cancer and dampening it in autoimmune diseases.
