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.