Deconvolution of developmental age refines thymic regulatory T cell ontogeny 3047

Abstract Description Continuous thymic T-cell selection and regulatory T (Treg) cell development challenges studies of their underlying mechanisms in native physiological conditions. Here, we develop a timestamp approach to trace thymic T-cell origins using Rag1CreER knockin mice combined with Rosa reporters. By resolving the developmental age, we define the processes, kinetics, and transcriptomics during thymic T-cell differentiation. We characterize how precursor cells expressing 4-1BB and/or CD25 are induced stochastically by TCR signaling to differentiate to Treg cells in vitro and in vivo. We specify thymic Treg maturation through CD73 upregulation, gene expression changes, and Treg-specific DNA demethylation. Furthermore, we determine the features of recirculating or retained mature thymic Treg cells. Thus, our deconvolution of developmental age refines thymic Treg cell ontogeny in native conditions, a foundation for further exploring the nature of thymic selection and Treg differentiation. Our strategy is also broadly applicable to resolving T-cell differentiation processes and related functional heterogeneity. Funding Sources This study was supported by the American Lebanese Syrian Associated Charities and the National Institutes of Health grants R21 AI146614 (Y. Feng) and R01 AI153138 (Y. Feng) and National Cancer Institute cancer center support grant P30 CA021765 (St. Jude Children’s Research Hospital). Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)