NEWS AND VIEWS 10. Hiraoka, N. et al. J. Biol. Chem. 279, 3058–3067 (2004). 11. McEver, R.P. Curr. Opin. Cell Biol. 14, 581–586 (2002). 12. Leppänen, A., Yago, T., Otto, V.I.,McEver, R.P. & Cummings, R.D. J. Biol. Chem. 278, 26391–26400
(2003). 13. Somers, W.S., Tang, J., Shaw, G.D. & Camphausen, R.T. Cell 103, 467–479 (2000). 14. Sperandio, M. et al. J. Exp. Med. 197, 1355–1363 (2003).
TH-17: a giant step from TH1 and TH2 Thomas A Wynn CD4+ T cells have been classically separated into two dominant effector populations: T helper types 1 and 2. Two new studies suggest that T cells producing interleukin 17 constitute a previously unknown lineage of CD4+ T cells.
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xpression of interleukin 17 (IL-17; also called IL-17A) has been linked to a growing list of autoimmune and inflammatory diseases such as rheumatoid arthritis, lupus, asthma and allograft rejection1–4. Mechanistically, IL-17 is believed to contribute to the pathogenesis of these diseases by acting as a potent proinflammatory mediator5. Although studies have suggested IL-23-stimulated CD4+ T helper type 1 (TH1) cells are the main source of IL-17 (refs. 2,4), the molecular mechanisms that govern the development of IL-17-producing cells (called ‘TH-17’ cells) have remained unclear. It has also been uncertain at what point during the development of effector T cells TH-17 cells ‘diverge’ from the classic TH1 population. Two reports in this issue of Nature Immunology challenge the idea of a shared developmental pathway for TH-17 and TH1 orTH2 cells and instead provide convincing evidence that TH-17 cells are a completely separate and early lineage of effector CD4+ TH cells produced directly from naive CD4 T cells6,7. Although the importance of IL-17-producing CD4+ T cells in autoimmune pathogenesis is now widely accepted1,4,8,9, the signaling pathways governing the development and maintenance of these cells has remained largely unknown. It is clear, however, that IL-23 is a key trigger for the production of IL-17 (ref. 3). Because IL-23 and IL-12 both use the IL-12p40 chain and interact with receptors that share the common IL-12 receptor β1-subunit (IL-12Rβ1), and because both TH1 (positive for interferon-γ (IFN-γ)) and TH-17 CD4+ T cells are often found in diseased tissues10,11, it has been widely believed that there is considerable overlap between the developmental pathways for producing effector TH1 and TH-17 cells5,8,12.
Thomas A. Wynn is at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. e-mail:
[email protected]
Old model IL-12Rβ1
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7. Hemmerich, S., Leffler, H. & Rosen, S.D. J. Biol. Chem. 270, 12035–12047 (1995). 8. Hemmerich, S. et al. Immunity 15, 237–247 (2001). 9. Uchimura, K. et al. J. Biol. Chem. 279, 35001–35008 (2004).
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Figure 1 Development of IL-17-producing effector CD4+ T cells (TH-17) by IL-23 is inhibited by IFN-γ and IL-4. Previously, TH1 and TH-17 cells were widely believed to arise from a common TH1 precursor (Old model). New data now suggest that TH-17 cells represent a completely separate lineage of CD4+ T cells that differentiate along a distinct developmental program that diverges early from the TH1 and TH2 lineages and is antagonized by the cytokines and signaling pathways that govern the development of TH1 and TH2 cells (New model). TH-17 cells trigger potent proinflammatory responses by upregulating chemokine production in important target cells such as fibroblasts. Notably, although IFN-γ-producing cells were originally thought to be the central mediators of autoimmune disease, the new data now suggest that IFN-γ and IL-4 (TH1 and TH2 effector molecules) function to directly antagonize the development of TH-17 cells, which are responsible for the destructive tissue pathology. These data strongly suggest that it may be more efficacious to target the activity of TH-17 cells directly, rather than targeting TH1 or TH2 cells, for the treatment of autoimmune and inflammatory disease.
Indeed, TH1 and TH-17 cells were believed to arise from a common TH1 precursor. However, because intracellular cytokine staining studies have demonstrated that there is little to no overlap between the cells expressing IL-17 and IFN-γ, the two developmental pathways must separate at some point. It has been unclear whether this divergence occurs early or late during the development of effector T cells and whether the actions of IL-23 are focused on naive CD4 T cells, fully differentiated effector CD4 T cells or both. Definitive proof for one of
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these models has been difficult to obtain because activation of naive CD4+ precursor cells does not usually lead to substantial development of TH-17 cells even when IL-23 is present5. The new work by Harrington et al.6 and Park et al.7 resolves those issues by showing that IL-23 can induce a sizeable pool of IL-17-producing cells if IFN-γ and IL-4 are neutralized. Harrington et al. used an in vitro approach, while Park et al. extended those findings by examining both the in vitro and in vivo development of TH-17 cells. Complementary results from both studies
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NEWS AND VIEWS clearly demonstrate that IL-23 can induce the differentiation of naive T cells into TH-17 cells through a mechanism that is distinct from the signals driving the development of TH1 cells (dependent on the transcription factors T-bet, STAT4 and STAT1) and TH2 cells (dependent on the transcription factors GATA-3 and STAT6), thus confirming TH-17 cells as a separate and early lineage of effector T cells, rather than cells differentiating directly from TH1 cells (Fig. 1). Harrington et al. first determined whether IL-23 stimulates IL-17 production in fully differentiated TH1 or TH2 cells. Notably, they found that IL-23 has little effect, thus providing some of the first evidence that IL-23 targets naive CD4+ T cells at a point preceding commitment to the TH1 or TH2 lineages. Moreover, unlike the generation of TH1 cells, the optimal generation of IL-17-producing effector T cells was independent of STAT1, T-bet or STAT4. Most notable, however, were further experiments showing that IFN-γ and STAT1 potently inhibit the development of TH-17 cells, thus providing a specific mechanism by which the TH1 developmental apparatus could actively suppress TH-17 cell development. These data also clearly demonstrate an early point of lineage divergence between TH1 and TH-17 effector cells. Furthermore, the data provide a basis for understanding how inhibition of IFN-γ signaling might be expected to enhance the development of pathogenic TH-17 effector cells and disease exacerbation in autoimmunity2,5. Park et al. used a similar approach and asked many of the same questions; however, they also examined the contributions of costimulatory molecules to the development of TH-17 cells. Consistent with the results of Harrington et al., they too found that IFN-γ actively suppresses the development of TH-17 cells. Park et al. also demonstrated that the development of antigenspecific TH-17 cells is highly dependent on both CD28 and ICOS costimulatory molecules. That result contrasts with those for TH1 cells, which develop normally in the absence of ICOS but are highly dependent on CD28-B7 signaling. These studies from both Harrington et al. and Park et al. provide strong evidence supporting the idea of early rather than late divergence of TH-17 and TH1 effector cells during CD4+ T cell development. Because type 1 interferons are capable of activating STAT1 signaling, Harrington et al. further hypothesized that type 1 interferons might share with IFN-γ the ability to inhibit TH-17 development. Notably, this speculation turned out to be correct, as their data suggest that type I interferons and possibly other STAT1-activating ligands do indeed inhibit the development of TH-17 effector cells, although to a lesser extent than IFN-γ does. They also
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explored the mechanism for IFN-γ-mediated suppression of TH-17 cells and found that IFNγ potently inhibits IL-23 receptor expression. Because deficiencies in STAT1 and T-bet failed to prevent IL-23-induced TH1 cell development, they speculated that IFN-γ might actively promote TH1 cell development by upregulating IL-12Rβ2 while simultaneously inhibiting TH-17 cell differentiation by downregulating the IL-23R. To test that hypothesis, they used IFN-γ receptor–deficient CD4+ precursor T cells and found that TH1-polarized IFN-γ receptor–deficient effector cells (driven by IL-12) expressed more IL-12Rβ2, whereas IL-23-stimulated IFN-γ receptor–deficient cells (IL-17 polarized) expressed much more IL-23R. Thus, in the absence of IFN-γR signaling, the addition of IL-12 or IL-23 preferentially stimulates IL-12Rβ2 or IL-23R expression, respectively. Given those data, Harrington et al. propose a mechanism of TH1–TH-17 lineage divergence in which STAT1 signaling activated by type 1 or type 2 interferon leads to the differential regulation of the IL-12R and IL-23R complexes. Unexpectedly, in addition to demonstrating the inhibitory effects of interferons, both papers show that IL-4 can also inhibit Th-17 development. Harrington et al. examined the regulatory effects of TH2 cells by comparing the frequency of IL-17 effector cells that developed from antigen-activated DO11.10 cells in IFN-γ-neutralizing conditions with or without exogenous IL-4 or monoclonal antibody to IL-4 (anti-IL-4). Notably, they found that IL-4 can suppress TH-17 cell development while at the same time promoting TH2 cell development. Thus, similar to results obtained in the studies with IFN-γ, IL-4-mediated TH2 cell development seemed to actively suppress TH-17 cell development. Park et al. did similar studies and found that a combination of IL-23 together with anti-IL-4 and anti-IFN-γ was the most potent ‘cocktail’ for generating TH-17 cells. The differentiation of IL-17-producing cells thus occurs most efficiently when TH1 and TH2 effector functions are simultaneously inhibited. In support of that conclusion, both studies determined that TH-17 cell development is independent of the STAT6 or STAT4 signaling molecules, further confirming the idea that TH-17 cells are a unique lineage of effector T cells whose differentiation is regulated by a developmentally controlled signaling pathway distinct from pathways required TH1 or TH2 differentiation. Finally, Harrington et al. also showed that mature TH-17 cells are relatively resistant to suppression by TH1 or TH2 cytokines, which indicates that the inhibitory effects of IFNγ and IL-4 are probably limited to the early stage of TH1–TH2–TH-17 differentiation. Park et al. reported similar results with IFN-γ;
however, they found that IL-4 could inhibit IL-23-dependent IL-17 production even in mature TH-17 cells. Thus, it remains uncertain whether TH-17 cells are as ‘terminally differentiated’ as mature TH1 and TH2 CD4+ T cells. Additional issues remaining include the timing of the acquisition of TH-17 cells during developing immune responses in vivo and under what circumstances IFN-γ and IL-4 responses would be inhibited, permitting the efficient development of IL-23-stimulated TH-17 effector cells. Also, are TH1 and TH2 effector cells more sensitive to downregulatory mechanisms (such as those from T regulatory cells or silencers of cytokine signaling), which might favor TH-17 cell differentiation? Other than IL-23, what additional signals are needed to maintain the population of effector TH-17 cells, and do memory TH-17 cells develop via the same developmental pathways as TH1 and TH2 memory cells? Finally, do TH1, TH2 and TH-17 cells produce and respond to distinct subsets of chemokines that might differentially regulate their recruitment to diseased tissues? Notably, Park et al. found that IL-17-stimulated embryonic fibroblasts upregulated over 60 unique genes, including many encoding chemokines. They also generated transgenic mice expressing IL-17 in lung epithelial cells and found that IL-17 overexpression induced substantial pulmonary pathology, which, as in the fibroblast studies, was associated with the production of more than 14 different chemokines. Finally, Park et al. showed that a neutralizing IL-17A-specific monoclonal antibody used either before or after disease was established could prevent the development of experimental autoimmune encephalomyelitis, further confirming the pathogenic nature of TH-17 cells. The improved understanding of the factors governing the development of TH-17 cells provided by the reports of Harrington et al. and Park et al. will spawn exciting new research and will accelerate progress toward the development of rational strategies for treating patients with autoimmune and inflammatory diseases. 1. Murphy, C.A. et al. J. Exp. Med. 198, 1951–1657 (2003). 2. Langrish, C.L. et al. J. Exp. Med. 201, 233–240 (2005). 3. Aggarwal, S., Ghilardi, N., Xie, M.H., de Sauvage, F.J. & Gurney, A.L. J. Biol. Chem. 278, 1910–1914 (2003). 4. Cua, D.J. et al. Nature 421, 744–748 (2003). 5. Kolls, J.K. & Linden, A. Immunity 21, 467–476 (2004). 6. Harrington, L.E. et al. Nat. Immunol. 6, 1123–1132 (2005). 7. Park, H. et al. Nat. Immunol. 6, 1133–1141 (2005). 8. Nakae, S. et al. Immunity 17, 375–387 (2002). 9. Nakae, S. et al. Proc. Natl. Acad. Sci. USA 100, 5986– 5990 (2003). 10. Oppmann, B. et al. Immunity 13, 715–725 (2000). 11. Parham, C. et al. J. Immunol. 168, 5699–5708 (2002). 12. Ye, P. et al. J. Exp. Med. 194, 519–527 (2001).
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