Fetal Alcohol Exposure and Immune Ontogeny
Principal Investigator: Brian Rudd
DESCRIPTION (provided by applicant):
In the United States, 20% of women have self-reported alcohol consumption during pregnancy, and 5% of live births manifest in fetal alcohol spectrum disorder. In humans, it has been shown that even limited alcohol exposure during gestation leads to impaired development of the immune system and an increased susceptibility to infection. Murine models of fetal alcohol exposure (FAE) have suggested that increased susceptibility to infection relates to defects in the adaptive immune system. In both humans and mice, FAE has been shown to decrease the number and function of CD8+ T cells; however, the underlying basis for why this occurs remains unknown. For example, it is not known whether FAE affects thymic output, survival of CD8+ T cells in the periphery, or homeostatic proliferation of cells prior to infection. We also lack critical information regarding the mechanisms underlying the altered behavior of CD8+ T cells during infection. In this study, we will use cutting-edge approaches to determine how fetal alcohol exposure limits the development of the CD8+ T cell compartment and impairs the host response to intracellular infection in adulthood. Our hypothesis is that FAE shapes the adult CD8+ T cell response to infection by altering the developmental layering of CD8+ T cells. In aim 1, we will use a novel fate mapping system to determine how FAE alters the numbers and phenotype of CD8+ T cells produced at different stages of life. In aim 2, we will determine how FAE-mediated changes to the adult CD8+ T cell compartment alter the host response to infection. Knowledge from these studies is expected to pave the way for the development of critical preventive and therapeutic strategies to boost immunity in FAE individuals.