The recent discovery of CD4 + T cells characterized by secretion of interleukin (IL)-17 (T H 17 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 H 1/T H 2 paradigm. T H 17 and nT reg cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis 1,2 . 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 H 17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T H 17 phenotype [3][4][5] . A second pathway has been discovered in which a combination of TGF-β and IL-21 is capable of inducing differentiation of mouse T H 17 cells in the absence of ). However, TGF-β and IL-6 are not capable of differentiating human T H 17 cells 2,9 and it has been suggested that TGF-β may in fact suppress the generation of human T H 17 cells 10 . 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 11 , although the factors required for differentiation of naive human CD4 to T H 17 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 H 17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T H 17 cells in human inflammatory disease.To better understand regulation of IL-17A secretion from human CD4 + T cells, we used a strategy that would allow us to evaluate the effects of various combinations of cytokine on expansion of T H 17 cells from memory T cells versus differentiation of naive CD4 + lymphocytes into T H 17 cells. Specifically, we used high-speed flow cytometry for sorting these two distinct populations of CD4 + T cells from the peripheral blood of healthy subjects: CD4 + CD25 − CD62L + CD45RA hi cells highly enriched for naive T cells and CD4 + CD25 − CD62L + CD45RA − cells enriched for central memory T cells (T CM ; Fig. 1a). All cells enriched for a naive or a central memory phenotype expressed the chemokine receptor CCR7 (data not shown). These two T cell populations were then stimulated with plate-bound

CD4+ T helper 1 (TH1) cells are important mediators of inflammation and are regulated by numerous pathways, including the negative immune receptor Tim-3. We found that Tim-3 is constitutively expressed on cells of the innate immune system in both mice and humans, and that it can synergize with Toll-like receptors. Moreover, an antibody agonist of Tim-3 acted as an adjuvant during induced immune responses, and Tim-3 ligation induced distinct signaling events in T cells and dendritic cells; the latter finding could explain the apparent divergent functions of Tim-3 in these cell types. Thus, by virtue of differential expression on innate versus adaptive immune cells, Tim-3 can either promote or terminate TH1 immunity and may be able to influence a range of inflammatory conditions.