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

Regulatory T cells (T cells) are critical regulators of adaptive immunity and the pathophysiology of antitumoral immunity. T 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 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 cells exhibit distinct dynamics but are both continuously replenished by de novo generation throughout life. The predominant precursors of circulating EM T cells are naive thymic T 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 cells specifically derive from preexisting EM T cells. In summary, we define a linear ontogeny of T cells from the thymus to EM, driven by self-antigen recognition, that then gives rise to tumor-infiltrating T cells.