The recent discovery of CD4⁺ T cells characterized by secretion of interleukin (IL)-17 (T_H17 cells) and the naturally occurring regulatory FOXP3⁺ CD4 T cell (nT_reg) has had a major impact on our understanding of immune processes not readily explained by the T_H1/T_H2 paradigm. T_H17 and nT_reg cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis^,. Our recent data and the work of others demonstrated that transforming growth factor-β (TGF-β) and IL-6 are responsible for the differentiation of naive mouse T cells into T_H17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T_H17 phenotype^,,. A second pathway has been discovered in which a combination of TGF-β and IL-21 is capable of inducing differentiation of mouse T_H17 cells in the absence of IL-6 (refs ). However, TGF-β and IL-6 are not capable of differentiating human T_H17 cells^, and it has been suggested that TGF-β may in fact suppress the generation of human T_H17 cells. Instead, it has been recently shown that the cytokines IL-1β, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4⁺ T cell lines isolated from human peripheral blood, although the factors required for differentiation of naive human CD4 to T_H17 cells are still unknown. Here we confirm that whereas IL-1β and IL-6 induce IL-17A secretion from human central memory CD4⁺ T cells, TGF-β and IL-21 uniquely promote the differentiation of human naive CD4⁺ T cells into T_H17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T_H17 cells in human inflammatory disease.