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Cellular & Molecular Immunology (2013) 10, 2–3 ß 2013 CSI and USTC. All rights reserved 1672-7681/13 $32.00 www.nature.com/cmi RESEARCH HIGHLIGHT One way to pathogenesis, many ways to homeostasis Linrong Lu1,2 and Jianli Wang1 Cellular & Molecular Immunology (2013) 10, 2–3; doi:10.1038/cmi.2012.51; published online 29 October 2012 C D4 T cells play central roles in both immune response and regulation. They can either serve as the mediators of adaptive immune response against infections, or act as gate keepers to maintain immune homeostasis. Upon activation by antigens, naive T cells proliferate and differentiate into different T helper (Th) cells with distinct effector functions. Th1 cells, induced by transcription factor T-bet and produce interferonc, are crucial for clearing intracellular pathogens. In contrast, IL-4 expressing Th2 cells driven by GATA-3 are responsible for the clearing of extracellular pathogens. Th17 cells, an additional subset of T cells expressing transcription factor RORct and cytokine IL17, are considered as the main drivers of autoimmune tissue injury. On the contrary, CD41FoxP31 regulatory T (Treg) cells, which can be generated either in the thymus or in the peripheral in respond to chronic challenges, are known to play key roles in maintaining immunological homeostasis and the control of autoimmune deviation or diseases. In a recent issue of Nature Immunology, two independent studies from Harvard Medical School described the transcriptional signature of effector Th17 and Treg cells and unveiled very different mechanisms in instructing these two cell types.1,2 Th17 cells are characterized by their capacities to produce IL-17A, IL-17F, IL-21 and IL-22. In vivo, these cells are present at the site of tissue inflammation in many autoimmune diseases and are thought to be the critical drivers of autoimmune tissue inflammation 1 Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China and 2Program in Molecular and Cellular Biology, Zhejiang University School of Medicine, Hangzhou, China Correspondence: Dr LR Lu, Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China. E-mail: [email protected] and Dr JL Wang, Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, China. E-mail: [email protected] Received: 21 September 2012; accepted: 24 September 2012 and damage. In vitro, IL-17 expressing cells can be differentiated by a combination of the cytokines transforming growth factor (TGF)-b1 and IL-6. However, Th17 cells induced by TGF-b1 and IL-6 in vitro do not readily induce autoimmune inflammation and need additional exposure to another cytokine IL-23 to become pathogenic.3 The analysis of IL-23R2/2 mice also revealed the essential role of the IL-23 signal in Th17 cell-mediated pathogenesis, since decreased Th17 function and reduced susceptibility to experimental autoimmune encephalomyelitis (EAE) were observed in those mice.4 However, how IL-23 drives pathogenic Th17 cells is yet to be clarified. In this issue of Nature Immunology, Lee et al., from Vijay K Kuchroo’s laboratory, identified TGF-b3 as a key downstream factor of IL-23 responsible for the driving of pathogenic Th17 cells. By using detailed microarray analysis of the gene expression in Th17 cells induced under different conditions, the authors first found that TGF-b3 was substantially induced in Th17 cells and this induction depended on the presence of the IL-23 signal, suggesting the role of TGF-b3 in IL-23 induced pathogenic differentiation of Th17 cells. This hypothesis was later proven by the experiments showing that Th17 cells could also be induced by using IL-6 plus TGF-b3 instead of TGF-b1. More importantly, TGF-b3-induced Th17 cells were as potent as Th17 cells induced by TGF-b1, IL6 and IL-23 for inducing EAE. Finally, the authors performed additional microarray analysis on Th17 cells induced by either TGF-b11 IL-61IL-23 or TGFb31IL-6 and defined the transcriptional signature of pathogenic Th17 cells, represented by 233 genes differentially expressed in pathogenic Th17 cells compared to non-pathogenic Th17 cells. Among which, 23 of them are closely relevant to the pathogenic functions of Th17 cells, including the elevated expression of distinct chemokines and cytokines (Cxcl3, Ccl4, Ccl5, Ccl3, Csf2, Il3, Il22 and Casp1), transcription factors Tbx21 and STAT4 and several effector molecules, such as Gzmb, Lag2 and Lglas. Pathogenic Th17 cells also downregulate the expression of IL-10, IL9, IL1Rn and Ikzf3, which are upregulated in non-pathogenic Th17 cells. Upregulation of Tbx1 (which encodes transcription factor T-bet) in pathogenic Th17 cells is also well consistent with the essential role of T-bet in the pathogenesis of Th17 cells. Interestingly, the defect of pathogenic Th17 cells in Tbx12/2 mice could be overcome by the treatment of TGF-b3, suggesting that T-bet might regulate the endogenous expression of TGF-b3. In summary, this study revealed the essential function of IL-23/TGFb-3 axis in driving pathogenic Th17 cells, as judged by their capacity to induce both the ‘pathogenic signature’ and the actual pathogenic functions of these cells. In the same issue of Nature Immunology, Fu et al., from Diane Mathis and Christophe Benoist’s laboratory, used a large scale transcriptome profiling analysis approach to study the signature of CD41FoxP31 Treg cells. The development of Treg cells in the thymus or induction of Treg cells in vitro is characterized and relies on the expression of transcription factor FoxP3. However, the transduction of FoxP3 or its induction by TGF-b in vitro is not sufficient to elicit the full Treg cell signature. In fact, FoxP3 has been reported to interact with many different transcription factors including NFAT, Runx1, Eos, Stat3, IRF4 and so forth, many of which are indeed found to be important for the development or full functions of FoxP31 Treg cells. However, we still don’t know how the contributions of these different factors are orchestrated in the process of Treg cells induction. The authors started with the analysis of a ‘Treg signature’ (composed of 603 target genes differentially expressed in canonical Treg cells) in 129 gene expression profiles from various CD41 T cells including cells from mice which are deficient in the expression Research Highlight 3 Th17 IL-23 T-bet? Non-pathogenic TGF-b3 Th17 Pathogenic Signature Pathogenic FoxP3 + Eos FoxP3 + IRF4 NaÏve T FoxP3 + GATA-1 Treg Treg Signature FoxP3 + Satb1 Locked in FoxP3 + Lef1 FoxP3 + X Figure 1 Driving pathogenic Th17 cells and stable Treg cells. (a) IL-23/TGF-b3 axis in driving pathogenic Th17 cells: IL-23 is essential for the stabilization of Th17 cells and their ability to induce autoimmune tissue inflammation through the induction of TGF-b3 expression in Th17 cells, which might be mediated by the activation of T-bet; (b) The multiple redundancy in the Treg cell induction: induction of stable Treg cells expressing full Treg signature required the expression of FoxP3 together with any one of the other factors, including Eos, IRF4, GATA-1 lef1 and Sabt1, etc. TGF, transforming growth factor; Treg, regulatory T. of the transcription factors that interact with FoxP3. By using the context likelihood of relatedness algorithm, the authors were able to align the key transcription factors according to their contribution ‘scores’ to the expression of this Treg signature. As expected, this analysis identified FoxP3 as the top predicted regulator with the highest score. It also revealed a number of other transcriptional regulators of the Treg signature, including Eos, Helios, Lef1 and GATA-1, some were shown previously to be associated with Treg cell function.5,6 The actual contributions of four transcription factors, Eos, GATA-1, Xbp1 and Helios, were then verified by direct expression profiling of Treg cells from the knockout mice of these genes. Surprisingly, the Treg signatures in each of these mutated mice were not altered significantly compared to wild-type cells. This finding was intriguing but consistent with the normal Treg cell numbers and functions in these mice as shown previously.7–9 However, this observation did not exclude the contributions of these factors to the stabilization of Treg cells. Indeed, when the authors overexpressed these factors together with FoxP3, they found that overexpression of FoxP3 alone only led to a small fraction of Treg signature genes, while the co-expression of any of these factors with FoxP3 was capable of inducing the full Treg signature robustly. Two inputs were thus needed to work synergistically to ‘lock in’ the Treg signature and the establishment of the stable Treg cell state. The ‘two key’ control system diminishes the risk of the erroneous activation of Treg cells under the circumstances when FoxP3 is transiently induced. More interestingly, as judged by the expression pattern of the ‘Treg signature’, five of the factors (including Eos, IRF4, GATA-1, Lef1 and Satb1) regulated the same set of genes together with FoxP3, which revealed the multiple redundancy of this lock-in process. It is worth mentioning that, although this study showed that the synergistic effect can be mediated by five different factors, the list might still be incomplete. This redundancy not only ensures additional stability, but also allows several different physiological pathways to arrive at the same state, which may be relevant to the different thymic and extra-thymic context of Treg cell differentiation. Different conditions might each induce one or another cofactor to enable a ‘lock-in’ of the Treg cell transcriptional network. Taken together, these two papers described the essential factors in driving or maintaining either pathogenic Th17 cells or Treg cells using the transcriptional signature as a marker. Both pathogenic Th17 cells and Treg cells are tightly controlled, since both Th17 and Treg cells require at least two different factors to reach a fully functional state (either to be pathogenic for Th17 cells or to be ‘locked in’ for stable Treg cells). Although a definitive surface marker is still not available, pathogenic Th17 cells and ‘locked-in’ Treg cells can now be defined by their transcription signature as described in both papers. Extensive analysis of these ‘expression signatures’ and associated experimental evidence in these two reports also leads to our understanding of the process or architecture of the differentiation of these cells, which are very different. Pathogenic Th17 cells are driven strictly by the IL-23/TGF-b3 axis. In contrast, Treg cells have multiple choices of many different factors or pathways (including, but not limited to, the five factors identified by Fu et al.) to fulfill their differentiation (Figure 1). These different regulation modes well represent the nature of the immune system. The immune system is doing its best to maintain homeostasis and prevent autoimmunity, which could be achieved by inducing Treg cells through many different ways under different circumstances or at different locations. For each deliberate immune response against infection, when an effective clearing of pathogens is necessary, the immune system also manages to keep the reaction well controlled to prevent excessive activation and self-destruction, which makes it crucial to keep the pathogenesis pathways well constrained in multiple steps. 1 2 3 4 5 6 7 8 9 Lee Y, Awasthil A, Yosef N, Quintana FJ, Xia S, Peters A, Wu C et al. Induction and molecular signature of pathogenic TH17 cells. Nature Immunol 2012; 13: 991–999. Fu W, Ergun A, Lu T, Hill JA, Haxhinastol S, Fassett MS et al. A multiply redundant genetic switch ‘locks in’ the transcriptional signature of regulatory T cells. Nature Immunol 2012; 13: 972–980. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B et al. Interleukin-23 rather than interleukin12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421: 744–748. McGeachy MJ, Chen Y, Tato CM, Laurence A, JoyceShaikh B, Blumenschein WM et al. The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 2009; 10: 314–324. Pan F, Yu H, Dang EV, Barbi J, Pan X, Grosso JF et al. Eos mediates Foxp3-dependent gene silencing in CD41 regulatory T cells. Science 2009; 325:1142–6. Beyer M, Thabet Y, Müller RU, Sadlon T, Classen S, Lahl K et al. Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nat Immunol 2011; 12: 898–907. Yu C, Cantor AB, Yang H, Browne C, Wells RA, Fujiwara Y et al . Targeted deletion of a high-affinity GATA-binding site in the GATA-1 promoter leads to selective loss of the eosinophil lineage in vivo. J Exp Med 2002; 195: 1387–1395. Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 2008; 320: 1492–1496. Cai Q, Dierich A, Oulad-Abdelghani M, Chan S, Kastner P. Helios deficiency has minimal impact on T cell development and function. J Immunol 2009; 183: 2303–2311. Cellular & Molecular Immunology