The global burden of disease caused by intracellular pathogens remains one of the great challenges facing the biomedical community. Such pathogens and their engineered variants could also be employed in acts of bioterrorism. The innate and adaptive components of the immune system enable organisms to target and eliminate pathogens or cells infected with them. Activation of the adaptive immune response to intracellular pathogens is orchestrated by T cells. A central hypothesis of this program project is that understanding how T cells detect antigen with extraordinary sensitivity and how T cell activation is regulated is a key for developing rational protocols for combating infections, autoimmune disorders, and bioterrorism agents. In particular, this knowledge should lead to the development of vaccines and novel forms of therapeutics to treat potentially deadly infections. Developing an integrated mechanistic understanding of the various processes involved in T cell activation presents formidable challenges. One challenge is that T cell activation involves processes that occur over a wide spectrum of length and time scales ranging from molecular recognition events (that occur on millisecond time scales) to proliferation of specific T cell clones in response to infection (which happens after several days). A second challenge is that each of these processes is the result of collective dynamic events involving many molecular and/or cellular components, and it is difficult to intuit mechanistic understanding by examining only a few experimental reporters. The purpose of this program project is to bring together a team of scientists (the Immune Response Consortium) who are committed to developing an integrated understanding of the multiscale processes pertinent to T cell activation in response to a real pathogen. We will pursue this goal by building on a new paradigm where all members of the team will work on different aspects of the same biological process using methods that bring together the physical and life sciences. Computational studies (rooted in the physical sciences) will be seamlessly integrated with in vitro and in vivo genetic and biochemical experiments to understand the adaptive immune response to the NIH Category B pathogen, Listeria monocytogenes.