Project Summary / Abstract The exposure to microbes in utero and after birth permanently programs an individual’s immune system and life- long disease risk. However, the relationship between microbial exposure and immune ontogeny remain poorly defined. We have developed a mouse model to better understand how the maternal microbial environment shapes the offspring’s immune system. Our preliminary data indicates that the timing of microbial exposure has a profound impact on susceptibility to intracellular pathogens later in life. Thus, a main objective of this proposal is to dissect out how maternal microbial exposure alters the development and function of the offspring’s CD8+ T cells. To accomplish this objective, we will use a number of cutting-edge approaches to test the hypothesis that microbial exposure programs immune susceptibility by altering the developmental layers of the CD8+ T cell response to infection. In the first, aim we will determine how microbial exposure changes the way the CD8+ T cell compartment is ‘put-together.’ Results from this aim will provide insight into how the composition and programming of CD8+ T cells in the offspring are linked to microbial exposure in the earliest days of life. In the second aim, we will examine how the amount and timing of microbial exposure alter the offspring’s response to intracellular pathogens. We are particularly interested in determining how microbial exposure during specific windows of development (in utero, post-natal) changes the offspring’s CD8+ T cell response to infection later in life. Our proposal aims to provide a new conceptual framework for understanding how microbial colonization in early life leads to life-long, potentially irreversible, changes in the offspring’s immune system. Knowledge gained from these studies is expected to broaden our fundamental understanding of immune development and cell- mediated immunity.