How autoreactive thymocytes differentiate into regulatory versus effector CD4+ T cells after avoiding clonal deletion

Thymocytes bearing autoreactive T cell receptors (TCRs) are agonist-signaled by TCR/co-stimulatory molecules to either undergo clonal deletion or to differentiate into specialized regulatory T (T reg ) or effector T (T eff ) CD4 + cells. How these different fates are achieved during development remains poorly understood. We now document that deletion and differentiation are agonist-signaled at different times during thymic selection and that T reg and T eff cells both arise after clonal deletion as alternative lineage fates of agonist-signaled CD4 + CD25 + precursors. Disruption of agonist signaling induces CD4 + CD25 + precursors to initiate Foxp3 expression and become T reg cells, whereas persistent agonist signaling induces CD4 + CD25 + precursors to become IL-2 + T eff cells. Notably, we discovered that transforming growth factor-β induces Foxp3 expression and promotes T reg cell development by disrupting weaker agonist signals and that Foxp3 expression is not induced by IL-2 except under non-physiological in vivo conditions. Thus, TCR signaling disruption versus persistence is a general mechanism of lineage fate determination in the thymus that directs development of agonist-signaled autoreactive thymocytes. Singer and colleagues show that the developmental fate of autoreactive CD4 + thymocytes is determined by the timing and duration of agonist signaling. Early agonist signaling induces clonal deletion, whereas late agonist signaling induces differentiation into Foxp3 + T reg cells or IL-2 + T eff cells depending on whether TGF-β disrupts TCR signaling.