The orchestration of an adaptive immune response relies on a succession of dynamic molecular and cellular events taking place in specialized micro-environments. The outcome of T cell responses against viruses or tumors is influenced by contact-dependent in formation exchanges between various lymphocyte subsets and antigen-presenting cells. While studies of lymphocytes removed from their normal environments provide an essential foundation for understanding the cellular responses to different stimuli, a full u nderstanding of lymphocyte biology, however, will require integrating the information obtained from studies of isolated lymphocytes with studies of how the cells behave in their native tissue environments. We propose to use state of the art real-time imagi ng techniques to visualize in live anesthetized animals, the initiation and the regulation of an immune T cell response as it happens. Specifically, intravital multiphoton imaging will be used in combination with other methodology to study four fundamental aspects of T cell biology in lymphoid organs and tumors i) the regulation of cell-cell interactions between T lymphocytes and dendritic cells in lymph nodes ii) the basis of CD4 and CD8 collaboration during T cell responses iii) the mode of action of regu latory T cells, a subset of lymphocytes endowed with the capacity to suppress T cell responses iv) the migration and cytolytic activity of CD8 T cells within established tumors, during spontaneous or induced anti-tumor T cell responses. Elucidating how the various immune cell subsets act together to regulate the outcome of T cell responses in vivo could help identify new means to manipulate the immune system to fight cancer and autoimmune diseases. In addition, our approach should provide a new tool to bett er understand the activity of anti-tumoral T cells and to measure the effects of some immunotherapeutic strategies.
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