A putative scheme for the development of regulatory T (TR) cells. TR and naïve conventional helper T cells (Th0) develop within a normal thymus through the processes of positive and negative selection. Precursor T cells of relatively high avidity trigger a TR cell developmental programme involving the activation of Foxp3, whereas T cell receptors of intermediate avidity yield Th0 cells. Additionally, regulatory cells can be peripherally generated (for example, Tr1 cells) when activated under tolerogenic conditions (for example, with immature dendritic cells). As yet it is unclear whether de facto Foxp3+ TR cells can be generated in the periphery or whether the Tr1 cells produced from conventional Th0 cells are equivalent to naturally present TR cells. IL, interleukin; TE cell, effector T cell; TGF, transforming growth factor.