A linear ontogeny accounts for the development of naive, memory, and tumor-infiltrating regulatory T cells in mice

Regulatory T cells (T_reg cells) are critical regulators of adaptive immunity and the pathophysiology of antitumoral immunity. T_reg cells are both generated during thymic development and induced from peripheral conventional T cells. How these distinct pathways contribute to the homeostasis of circulating T_reg cells in health and disease remains unclear. We addressed this question using multiple fate-mapping mouse systems and modeling. Naive and effector/memory (EM) T_reg cells exhibit distinct dynamics but are both continuously replenished by de novo generation throughout life. The predominant precursors of circulating EM T_reg cells are naive thymic T_reg cells and not conventional T cells, a process driven by self rather than foreign antigen recognition. Using the same fate reporters and three tumor models, we demonstrate that infiltrating T_reg cells specifically derive from preexisting EM T_reg cells. In summary, we define a linear ontogeny of T_reg cells from the thymus to EM, driven by self-antigen recognition, that then gives rise to tumor-infiltrating T_reg cells.