Aging correlates with a marked susceptibility to infectious diseases. The progressive decline with age of the immune system - immunosenescence - is the primary underlying cause of this increased susceptibility. Important gaps remain in our understanding of the fundamental nature of immunosenescence, as well as in our practical ability to protect older adults against infectious diseases. Some of these result from the insufficient integration of the available models in which to research immunosenescence, and incomplete validation of the relevance of obtained data to the human aging. This proposal seeks to reduce this gap by a concerted effort to integrate human and mouse models and study memory T cell response in the skin of healthy young and old donors. In a novel human model, we have identified a significant defect in older adults in delayed-type hypersensitivity (DTH) responses to tuberculin antigens (Ag) by cutaneous CD4 memory T-cells. This has led to our central hypothesis: that one of the main age-related defects in immunity is the inability to efficiently direct Ag-specific memory responses to the sites of initial microbial challenge (skin, mucosa). We will test this hypothesis using a combination of complementary mechanistic mouse and human studies, designed to cross-inform each other, and always ultimately verifying the mechanisms in humans. PUBLIC HEALTH RELEVANCE: Infectious diseases inflict heavy toll upon the rapidly aging society with regard to lost productivity, mounting health costs and loss of life. At the conclusion of these studies, we expect that they not only will strongly contribute to our mechanistic understanding of age associated defect in immunity, but that their translational nature will offer insight into how to boost the attenuated immune responsiveness in old humans.