DESCRIPTION (provided by applicant): Maintaining diverse repertoires of naive and memory T cells provides vital protection against both novel and previously-encountered pathogens, and loss or dysregulation of these populations has catastrophic implications for health. However, while we have qualitative knowledge of the signals that in¿uence T cell division and survival, we
lack an integrated understanding of the mechanisms that regulate the sizes and T cell receptor (TCR) diversities of T cell compartments. Solving this `immuno-ecology` problem, and developing validated, quantitative models of the dynamics of our T cell repertoires, will give a basis for therapies in many areas; reversing the collapse in TCR diversity with age, which may impair responses to vaccines and infections; aiding T cell reconstitution following bone marrow transplants; treating dis- orders that disrupt homeostasis, such as leukemia's and HIV infection; and designing vaccines that boost immunity without impairing T cell memory to other pathogens. The goals of this project are (i) to fully characterize the rules governing the incorporation of new cells from the thymus into our naive T cell pools, identify age-related heterogeneity in naive T cell kinetics, and establish the impact of such heterogeneity on cell's functional responsiveness; and (ii) to extend this focus to memory T cell subsets to identify the rules governing birth and death within each. To achieve these goals we will use a combination of mathematical modeling and dedicated experiments in mice, connecting our results to mechanisms of T cell homeostasis in humans wherever possible. Achieving the aims of this proposal will be a long stride towards our long-term goal of an integrated, validated and quantitative model of human T cell homeostasis.