Project Summary/Abstract T cells coordinate systemic immunity and are essential for defense against viral and bacterial infections and tu- mors. The long-term goal of our research program is to employ innovative experimental genomics to build multi- dimensional data resources and develop new computational methods that we will use to obtain a comprehensive understanding at a molecular level of T cell activation and differentiation in response to various stimuli. We will address specific problems about T cell commitment to functional fates across contexts, regulatory mechanisms of these processes and their underlying transcription factors. Unprecedented resolution and statistical power will allow us to study similarities and differences of these mechanisms between T cell lineages and subpopulations, and generalizability of these observations from mouse to human. This goal will be achieved by executing three projects. We will study regulation of T cell activation and functional commitment in lymphocytic choriomeningi- tis virus (LCMV) infection model with a focus on the progenitor TCF1+ T cells (Project 1), transcriptional and epigenetic regulation and higher order chromatin organization in Treg cells (Project 2). Finally, we will build a database, methods, software and interfaces for comparative analysis of regulatory genomics data across mouse models and humans, allowing many fundamental and translational applications (Project 3). These studies will lead to future research and development of new therapeutic transcription factor and other targets and modulation strategies in diseases of dysregulated T cell immunity. Our data resources and methods will enable systematic data exploration, generation and validation of new specific hypotheses about molecular mechanisms of T cell function, and will provide a platform for mapping and analyzing new T cell data from new systems that we and others will generate in the future.