This renewal of the program project "Modulation of biodefense responses to microbial pathogens" is composed of four projects and three cores focused on the immune response to Category B and C Biodefense Pathogens and their products. The program theme is to define the parameters for development of protective immunity against viral and bacterial pathogens and their products. The central hypothesis is that early events in T cell activation determine whether or not long-term immunity is induced in response to vaccination, or whether damage is initiated in response to a bacterial toxin. Each project focuses on a unique aspect of the theme to deepen our understanding of the immune response to infectious agents. Project 1 (Lefrancois) proposes to investigate the mechanisms by which attenuated Listeria monocytogenes vaccines induce CD8 T cell immunity. T cell-DC interactions and the role of CD4 T cell help will be examined using in vivo systems including in situ microscopy and novel reporter mice. Project 2 (McSorley) will examine development of CD4 memory T cells in response to different forms of Salmonella infection and vaccination and will define the critical requirements for protective immunity to secondary typhoid. Project 3 (Vella) is centered on understanding how T cell activation by pulmonary administration of Staphylococcus aureus enterotoxin impacts the pathological mucosal response. Project 4 (Cauley) seeks to understand the impact on pulmonary influenza virus infection of the interaction between T cell responses and antibody. Components of all four projects are aimed at examining the induction of T cell responses to microbial agents in mucosal and peripheral sites and to understanding the complex interplay between the cellular participants of each response. The projects utilize in vivo models and in-depth cellular immunological techniques and are supported by 3 cores: administrative, flow cytometry and fluorescence microscopy/immunohistochemistry. The projects and cores synergistically interact and mutually reinforce one another to achieve the goals of the program. Coupled with strong institutional support, it is anticipated that significant new insights in immune response regulation to pathogens and their byproducts will continue to be obtained.