DC-CD4 interactions in Th2 differentiation

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The effector functions of CD4+ T cells are required for the immune response to helminths such as Trichuris and Schistosoma. CD4+ T cells are activated by major histocompatibility complex (MHC) class II molecules expressed by the hematopoietic antigen presenting cells (ARC), dendritic cells, macrophages, and B cells. The specific requirement for individual MHC class ll-positive APCs during CD4+ T cell-dependent control of parasites has not been fully elucidated. We have developed transgenic CD11c/Abeta(b) mice in which MHC class II l-Ab expression is targeted specifically to DCs; this pattern of class II expression is sufficient for development of primary Th1 responses to nominal antigen and control of subcutaneous Leishmania infection. In contrast, the sufficiency of dendritic cell antigen presentation in the development of Th2 responses is less clear. For example, B cells are required for the generation of Th2 responses to nominal and parasitic antigens and control of the gastrointestinal nematode, Trichuris muris. We propose to utilize the CD11c/Abeta(b) model to examine the sufficiency of antigen presentation by MHC class ll-positive DCs to CD4+ T cells in the generation of Th2 responses. We have three Specific Aims. In Specific Aim I, we will examine Th2 responses to the model antigens, ovalbumin and Schistosomal egg antigen. In Specific Aim II, we will ask if class ll-dependent interactions between DC and CD4+ T cells drive resistance to Trichuris muris nematode infection. Finally, we will ask if DC antigen presentation regulates the switch from Th1 to Th2 polarization which occurs during the immune response to Schistosoma mansoni. These pilot experiments will determine if DC-dependent antigen presentation generates protective antigen-specific immune responses against parasitic infections and will elucidate pathways to target in vaccine development.