' Interleukin 17 (IL-17)–producing T helper cells (TH-17 cells) are now
 accepted as the main population of pathogenic T cells driving
 autoimmune diseases such as experimental autoimmune encephalo
myelitis (EAE)1,2 and collagen-induced arthritis3, the mouse models
 for multiple sclerosis and rheumatoid arthritis, respectively. TH-17
 cells are characterized by their STAT3-dependent expression of the
 transcription factor RORgt4 and production of the hallmark cytokines
 IL-17 and IL-22 (ref. 5). Initial work to identify the factors involved in
 the differentiation of the TH-17 cell lineage has provided two observa
tions. First, IL-23 drives the production of IL-17 by memory T cells6.
 Second, in mice with a genetic deficiency of IL-23, resistance to EAE
 correlates with the lack of IL-17-producing T cells in the central
 nervous system (CNS)1. Subsequent studies showed that TGF-b, when
 combined with proinflammatory cytokines such as IL-6, is the
 strongest inducer of RORgtproteinandTH-17 cells in mice2,7,8. In
 contrast, transforming growth factor-b (TGF-b) alone drives expres
sion of the lineage-specific transcription factor Foxp3, leading to a
 regulatory T cell (Treg cell) phenotype2. In vitro, IL-23 seems to be not
 involved in the early differentiation of TH-17 cells, most probably
 because of the small amounts of the receptor for IL-23 (IL-23R) on
 naive T cells. Ligation of the T cell antigen receptor (TCR) in the
 presence of IL-6 has been shown to upregulate IL-23R4,althoughIL-6
 may not be the only factor able to do this.
 Consistent with the idea that this population is a distinct helper cell
 lineage, the differentiation of TH-17 cells is inhibited by the T helper
 type 1 (TH1) and TH2 hallmark cytokines interferon-g (IFN-g)and
 IL-4, respectively9. IL-27 and IL-25, originally defined for their
 TH1- and TH2-promoting activities, also regulate TH-17 cells10–12,
 although this does not seem to occur through the induction of IFN-g
 or IL-4. In a further twist, TH-17 cells have again been shown to have
 intimate links with Foxp3-expressing Treg cells, with both IL-2 (through
 STAT5) and retinoic acid (binding to RORgt) acting to negatively
 regulate RORgt while promoting Foxp3 (refs. 13,14). It seems that
 most of these factors regulate the early differentiation of TH-17 cells.
 Thus, despite being induced by the ‘anti-inflammatory’ TGF-b, the
 TH-17 population is rigorously regulated by many pathways.
 There is an unresolved contradiction in the data on TGF-b and
 inflammatory diseases such as EAE. Studies have shown convincingly
 that TGF-b is required for TH-17 differentiation in vitro and in vivo.
 Experiments have shown that TGF-b signaling is required by CD4+
 T cells for the induction of pathogenic TH-17 cells in vivo and
 furthermore that blocking TGF-b locally at the time of immunization
 abrogates EAE induction15. It has also been reported that, un
expectedly, expression of TGF-b under control of the Il2 promoter
 in a myelin oligodendrocyte glycoprotein (MOG)–specific T cell
transgenic mouse leads to exacerbated EAE because of greater num
bers of TH-17 cells2. However, there is a substantial body of evidence
 showing that TGF-b has anti-inflammatory effects in the same disease
 settings. TGF-b has been noted to increase during the remission phase
 of EAE16, andTGF-b-producing T cells can mediate oral tolerance
 in this disease17,18. Amelioration of EAE and collagen-induced
 arthritis has also been achieved by administration of soluble TGF-b1
 (refs. 19,20); conversely, systemic administration of antibodies
 blocking TGF-b in vivo leads to exacerbation of EAE15.Thesestudies
 were mostly done before TH-17 cells ‘appeared on the scene’; hence,
 they assumed effects on TH1 cells and now deserve reconsideration.