Foxp3⁺ CD4⁺ CD25⁺ regulatory cell (Treg) subsets that maintain immunologic homeostasis have been considered to be a homogeneous population of naturally occurring, thymus-derived CD4⁺CD25⁺ cells (nTregs). However, similar Foxp3+ Tregs can be induced from CD25⁻ precursors in vivo, and ex vivo with interleukin 2 (IL-2) and transforming growth factor β (TGF-β) (iTregs). These two subsets differ in their principal antigen specificities and in the T-cell receptor signal strength and co-stimulatory requirements needed for their generation. However, whether iTregs have any unique functions in vivo has been unclear. Although IL-6 can convert nTregs to Th17 cells, iTregs induced by IL-2 and TGF-β are resistant to this cytokine and thereby might retain suppressive function at inflammatory sites. Thus, nTregs and iTregs may have different roles in the adaptive immune response.