'TGF-b and IL-6 are required for the lineage commitment of TH-17
 cells. However, these two cytokines are unlikely to be sufficient to
 promote the full differentiation of inflammatory TH-17 cells, as
 suggested by studies of IL-23- or IL-1R1-deficient mice25,26. Our
 study here has shown that continued exposure of effector cells to
 TGF-b and IL-6 drove the production of IL-17 but not the production
 of important proinflammatory mediators such as IL-22 and chemokines. In addition, these cells produced IL-10, which most likely is
 important in regulating the magnitude of the potentially destructive
 TH-17 cell–mediated response. How then are the pathogenic TH-17
 cells in autoimmune inflammation derived? It seems that these
 cells become pathogenic through a switch in the balance of
 predominant signals received from TGF-b and IL-6 to those received
 from IL-23.  Initial TH-17 differentiation in the presence of TGF-b may result in
 ‘early’ effector cells that produce IL-17 but also IL-10 and small
 amounts of proinflammatory factors. Therefore, evaluation of IL-17  production alone may not indicate the true effector capacity of TH-17
 cells. We propose that this type of early TH-17 cell may be involved in
 homeostatic maintenance in the gut35, the only site identified so far to
 have a population of naturally occurring IL-17+ T cells4. However, it is not apparent whether these TH-17 cells driven by TGF-b and IL-6
 would be sufficient to mediate protective immunity against bacterial
 pathogens. It has been shown that during infection of mice with the
  intestinal pathogen Citrobacter rodentium,TH-17 cells are present in
 the absence of IL-23, but clearance of the infection requires IL-23
 (ref. 8). Whether these effects of IL-23 are on innate cells, as has been described in several colitis models, or on the TH-17 cells  themselves has not been defined. It is possible that additional IL-23 driven TH-17 factors are required for control of this infection.  TGF-b has long been associated with anti-inflammatory functions,
 particularly in regulating pathogenic TH1 responses. We found that
 IFN-g expression before transfer and the proportion of IFN-g+ cells in
 the CNS after transfer were decreased by exposure to TGF-b and IL-6.
 In contrast, IL-23 did not seem to inhibit IFN-g expression, and we
 consistently noted a high frequency of IL-17+IFN-g+ ‘double-positive’
 CD4+ cells in the CNS during active EAE. However, IFN-g-knockout
 mice are fully susceptible to EAE39, and neutralization of IFN-g during
 passive transfer exacerbates rather than reduces the severity of EAE1.
 Hence, the reduction of IFN-g by TGF-b and IL-6 is unlikely to
 substantially alter the pathogenic function of these cells.  Can TGF-b also regulate already activated pathogenic TH-17 cells?
 Many TH-17 cell–mediated inflammatory diseases have a relapsing-
remitting course, suggesting that regulation of these cells is possible.  Our studies here have suggested that exposure of pathogenic TH-17
 cells to TGF-b and IL-6 in peripheral sites of inflammation may
 enhance their production of IL-17. However, IL-10 production would
 concomitantly be induced, whereas the production of chemokines
 such as CCL2 (MCP-1) and CCL5 (RANTES) that attract inflamma
tory macrophages would be much lower. The overall effect would be  the downregulation of an ongoing effector TH-17 response and a
 reduction in the recruitment of inflammatory cells into the site. This
 would fit with what is found in relapsing-remitting EAE: at the peak of
 the initial disease course, TGF-b, IL-6 and IL-23 are all produced by dendritic cells in the CNS40, and newly generated effector TH-17 cells
 are proposed to be activated against new myelin epitopes at this
 time40,41. However, in these same conditions, the initiating TH-17 cell
driven response is controlled and there is a remission period until the
 next wave of T cells sets up a subsequent course of inflammation and
 relapse occurs.  What are the sources of TGF-b in vivo that probably regulate the
 generation and function of TH-17 cells? In vitro,Foxp3+ Treg cells are
 sufficient sources of TGF-b for the polarization of TH-17 cells7,42.
 TGF-b is also important in the biology of Treg cells and as a survival
 factor for mature Treg cells43, and it may also induce the differentiation
 of Foxp3+ Treg cells from naive T cells44,45. In vivo,CD4+ Tcellsarea
 crucial source of TGF-b for the generation of TH-17 cells46, although it
 remains to be definitively proven that Treg cells ‘drive’ TH-17 cells
 in vivo.Foxp3+ Treg cells are thought to be important in the recovery
 from EAE47, and diminished Treg cell numbers or function has been  associated with susceptibility to autoimmunity in mouse and
 human48–51, suggesting that Treg cells may also ‘restrain’ TH-17 cells.
 Thus, the clinical outcome is probably dictated by the balance of
 signals that a TH-17 cell receives, which in turn reflects the numbers
 and activity of Treg cells versus proinflammatory T cells present in the
 local environment.  In our study here, it was notable that IL-23-driven upregulation of
 IL-22 was not inhibited substantially by TGF-b and IL-6, which
 indicated that an intermediate TH-17 cell type may exist that produces
 not only IL-17 and IL-22 but also IL-10. Hence, the balance of TH-17
 cell effector states during a response may determine the amount of
 bystander damage: many cells producing IL-10 under the influence of
 TGF-b and IL-6 would cause minimal destruction; conversely, a
 predominance of TH-17 cells producing the full range of proinflam
matory factors in the absence of IL-10 would become highly destruc
tive. A similar self-regulating effect has been described for TH1 cells:
 during infection with Toxoplasma gondii or Leishmania major, IFN-g
producing T-bet+Foxp3– TH1 cells are required to also produce IL-10
 to avoid bystander immunopathology31,32. In thesemodels, IL-10
 seems to be induced in effector TH1 cells in conditions of strong
 inflammatory stimuli. In fact, we noted a further increase in IL-10
 production induced by TGF-b and IL-6 when IL-23 was also present,
 and we found that IL-1 similarly potentiated IL-10 production along
 with TGF-b and IL-6 (unpublished observations). We also found that
 IL-10 induced early in naive T cells stimulated with anti-CD3 in the
 presence of TGF-b and IL-6 was dependent on the addition of anti
CD28 (data not shown), further supporting a model in which strong
 stimulation conditions result in the coexpression of IL-10 and Il-17.
 In conclusion, we propose that TGF-b and IL-6 are involved in not
 only the induction but also the regulation of TH-17 cells. TGF-b may
 be produced by many cell types, and Treg cells may be one source of
 TH-17 cell regulation. If the balance between proinflammatory and
 regulatory signals is shifted, such as through decreased numbers of Treg
 cells, IL-10 production may be lost concomitant with an upregulation
 of proinflammatory mediators. Such ‘unrestrained’ cells would then
 be ‘armed’ to establish the immune pathology that has now been
 attributed to this subset of helper T cells.' bullet point this