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underway. Agents that target the self-renewal machinery of CSCs, such as PTC-209, add to this growing armamentarium. The relative rarity of CSC populations in many tumors highlights the need to develop new clinical trial designs and biomarkers to assess the utility of CSC-targeting agents. Ultimately, randomized clinical trials will be required to determine whether effective targeting of CSCs improves patient outcome.

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COMPETING FINANCIAL INTERESTS The author declares competing financial interests: details are available in the online version of the paper.

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Figure 1 BMI-1–mediated regulation of CSC self-renewal. Expression of the polycomb protein BMI-1 is regulated by multiple signal transduction pathways, including the Akt, Wnt, Notch, Hedgehog (Hh) and receptor tyrosine kinase (RTK) pathways. BMI-1 expression is negatively regulated by miRNAs such as mir-200C. BMI-1 complexes with other PRC1 and PRC2 proteins that repress the expression of genes bearing H3K27 histone marks, including those encoding INK4A/ARF and HOX. These pathways interact with EMT transcription factors including TWIST to regulate EMT and CSC self-renewal. Kreso et al.1 now identify a small molecule, PTC-209, that inhibits BMI-1 expression, thus inhibiting CSC self-renewal and tumorigenesis. SMO, Smoothened; FZ, Frizzled.

for their survival, and it has been proposed that other tumorigenic cell populations show this dependence. In addition, previous preclinical studies have suggested that CSC-targeting agents will have the greatest efficacy when they are administered early or in an adjuvant setting

alongside a primary therapy15. It will therefore be interesting to explore the efficacy of PTC209 in such settings. The CSC model has profound clinical implications. Several dozen early-phase ­clinical ­trials aimed at targeting CSCs are now

1. Beck, B. & Blanpain, C. Nat. Rev. Cancer 13, 727–738 (2013). 2. Enderling, H., Hlatky, L. & Hahnfeldt, P. Front. Oncol. 3, 76 (2013). 3. Kreso, A. et al. Nat. Med. 20, 29–36 (2014). 4. Meacham, C.E. & Morrison, S.J. Nature 501, 328–337 (2013). 5. Schepers, A.G. et al. Science 337, 730–735 (2012). 6. Vermeulen, L. et al. Nat. Cell Biol. 12, 468–476 (2010). 7. Cao, L. et al. J. Cell. Biochem. 112, 2729–2741 (2011). 8. Shimono, Y. et al. Cell 138, 592–603 (2009). 9. Glinsky, G.V., Berezovska, O. & Glinskii, A.B. J. Clin. Invest. 115, 1503–1521 (2005). 10. Rizo, A., Dontje, B., Vellenga, E., de Haan, G. & Schuringa, J.J. Blood 111, 2621–2630 (2008). 11. Liu, S. et al. Cancer Res. 66, 6063–6071 (2006). 12. Siddique, H.R. et al. PLoS ONE 8, e60664 (2013). 13. Schott, A.F. et al. Clin. Cancer Res. 19, 1512–1524 (2013). 14. Chen, K., Huang, Y.H. & Chen, J.L. Acta Pharmacol. Sin. 34, 732–740 (2013). 15. Korkaya, H. & Wicha, M.S. Cancer Res. 73, 3489–3493 (2013).

Good guys gone bad: exTreg cells promote autoimmune arthritis Nicole Joller & Vijay K Kuchroo Under most circumstances, Foxp3+ regulatory T (Treg) cells are a stable T cell population essential for maintaining self-tolerance. A study now shows that the inflammatory environment in autoimmune arthritis induces conversion of a subset of Foxp3+ T cells into interleukin-17–producing cells that contribute to disease pathogenesis (pages 62–68). CD4+Foxp3+ Treg cells suppress aberrant and excessive immune responses that induce tissue inflammation and autoimmunity. Under physio­ logical conditions, a number of mechanisms ensure sustained Foxp3 expression and Treg Nicole Joller and Vijay K. Kuchroo are at the Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. e-mail: [email protected]

cell stability1,2; however, during inflammation, some Treg cells may lose their ability to express Foxp3 as well as their regulatory function, thus acquiring characteristics of effector T cells3. Many autoimmune diseases, including rheumatoid arthritis, multiple sclerosis and type 1 diabetes, are characterized by loss of Treg cell numbers or their function4. In this setting, proinflammatory T helper type 1 (TH1) and/ or TH17 effector cells accumulate while Treg cell function is lost, resulting in an unfavorable shift

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in the Treg cell/effector T cell balance. In this issue of Nature Medicine, Komatsu et al.5 show that the local inflammatory milieu shifts this balance not only by promoting TH17 cell differentiation but also by converting a Foxp3+ subset into IL-17 producers that thereby contribute to pathogenesis in autoimmune arthritis (Fig. 1). The investigators found double-positive IL-17+Foxp3+ T cells in the synovial membrane of individuals with rheumatoid arthritis (RA)4. Using Foxp3-fate reporter mice, they identified 15

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Figure 1 Inflammatory conditions during arthritis convert a subset of Foxp3+ T cells into pathogenic TH17 cells. Komatsu et al.5 identify an unstable CD25lowFoxp3+ Treg cell set that loses Foxp3 expression during autoimmune arthritis. A feed-forward loop is established in which IL-6 secreted by synovial fibroblasts induces conversion of this subset of Treg cells into pathogenic TH17 cells, which in turn induce more IL-6 release through IL-17 secretion. Like fibroblasts and osteoblasts, TH17 cells derived from Foxp3+ T cells can produce high levels of RANKL, which directly promote osteoclastogenesis and bone destruction.

an unstable CD25lowFoxp3+ T cell subset, of which about half the cells lose Foxp3 expression and acquire a pathogenic TH17 phenotype under the inflammatory conditions in collagen-induced arthritis discovered in the study. Secretion of the TH17 differentiation factor IL-6—but not tumor necrosis factor-α (TNF-α) or IL-1β—by arthritic synovial fibroblasts at the joints drives the conversion of Foxp3+ T cells into pathogenic TH17 cells. In addition, in their mouse model, the authors uncovered a positive feed-forward loop at the arthritic joint where the production of IL-6 from these fibroblasts induced IL-17 production by the formerly Foxp3+ TH17 cells; IL-17 in turn induced more IL-6 from the synovial fibroblasts5. The conversion of Foxp3+ T cells into TH17 cells and the subsequent establishment of this feed-forward loop only occurred at inflamed joints, as immunization of mice with irrelevant antigen did not result in substantial Treg cell instability. This finding is in line with a recent report in which Treg cells were found to lose Foxp3 expression in the inflammatory setting of experimental autoimmune encephalomyelitis, a mouse model for multiple sclerosis6. Treg cells also acquired effector T cell characteristics and seemed to promote disease in a self antigen–driven manner. The authors went on to investigate the contribution of the converted cells to bone destruction 16

characteristic of RA. In vitro, TH17 cells derived from Foxp3+ T cells (‘exTreg cells’) produced higher levels of receptor activator of nuclear factor κB ligand (RANKL), a central cytokine for osteoclast activation and differentiation7, compared to regular in vitro–differentiated TH17 cells. Moreover, unlike other TH17 cells, IL-17–producing exTreg cells promoted osteoclastogenesis even in the absence of synovial fibroblasts and could thereby directly promote bone resorption5. Adoptive transfer experiments also revealed that CD25lowFoxp3+ T cells, which are prone to losing Foxp3 expression, not only were unable to suppress collagen-induced arthritis in mice but also accelerated arthritis more efficiently than total effector T cells or even memory cells, marking them as a highly pathogenic T cell population5. Compared to effector T cells, Treg cells are thought to have a higher-affinity T cell receptor repertoire that is biased toward self antigens. On the basis of the data shown by Komatsu et al.5, one could speculate that high-affinity self-reactive T cells that have started to express Foxp3 and under noninflammatory conditions would differentiate into bona fide Treg cells but would lose Foxp3 expression in the inflammatory setting of RA and become highly potent effector cells. However, further studies are needed to conclusively address this point.

The current study addresses two important points regarding the role of Treg cells in inflammatory autoimmune diseases. First, the significance of Treg cell stability and the inflammation-induced reprogramming of Treg cells into effector T cells in disease has recently been hotly debated and remains controversial. A number of studies in different settings suggest that natural Treg cells are an essentially stable population once they have committed to the lineage1,8,9, but considerable differences in the number of exTreg cells were observed both in the steady state and under inflammatory conditions. This may reflect differences in the fate reporter mice used by different groups, which most likely have different thresholds for the genetic labeling of cells that transiently express Foxp3. Whereas Foxp3 is primarily expressed in bona fide Treg cells, promiscuous, transient Foxp3 expression has also been observed in conventional T cells8,9. Several factors have been suggested to contribute to full Treg cell lineage commitment and sustained stable Foxp3 expression, including high expression of CD25 and CTLA-4, as well as multiple redundant transcriptional mechanisms and epigenetic modifications2,9,10. The study by Komatsu et al.5 confirms the importance of high CD25 expression for fully differentiated Treg cells, as CD25low but not CD25high Foxp3+ T cells lost Foxp3 expression during autoimmune arthritis. CD25lowFoxp3+ T cells may therefore represent a population of not yet fully committed Treg cells that are still plastic and can convert into effector cells under inflammatory conditions. Previous studies have shown that Treg cells adapt to the local cytokine environment and acquire transcription factors, chemokine receptors or cytokines characteristic of the effector T cells generated in this environment. For instance, T-bet, CXCR3 and interferon-γ expression in Treg cells is seen at sites of TH1 responses11, and RORγt, CCR6 and IL-17 expression in Treg cells is observed in the context of TH17 cell responses12. If the induction of these features is paired with Foxp3 instability, the acquisition of these proinflammatory features could give rise to a highly pathogenic effector T cell population, as shown by Komatsu et al.5. Second, the authors further elucidated what factors contribute to the balance between Treg cells and TH17 cells. IL-6 affects the Treg cell/TH17 cell balance by inducing de novo TH17 cell differentiation13,14, and the current study now shows that this effect is further enhanced by the ability of IL-6 to convert an unstable Treg cell population into pathogenic TH17 cells. Therapeutic approaches that aim at restoring the Treg cell/TH17 cell balance in autoimmunity would therefore ideally interfere

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with differentiation of pathogenic T cell subsets and maintain or restore Treg cell stability and function. Inhibition of TH17 differentiation and conversion of Treg cells into TH17 cells could be achieved by interfering with IL-6 signaling. Furthermore, a recent study showed that antagonizing TNF-α can restore Treg cell function in RA15, which is consistent with recent data showing that IL-6 and TNF-α interfere with Treg cell function at the site of tissue inflammation16. Combining blockade of TNF-α and IL-6 with drugs that maintain the epigenetic modifications in Foxp3+ Treg cells might therefore allow for the stabilization

of Foxp3+ Treg cells and thereby restore the Treg cell–TH17 cell balance through multiple synergistic mechanisms. The next generation of therapies in auto­ immune diseases should not only try to dampen proinflammatory cytokines but also promote Treg cell stability and function to mediate complete and lasting resolution of an autoimmune disease. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. 1. Rubtsov, Y.P. et al. Science 329, 1667–1671 (2010). 2. Fu, W. et al. Nat. Immunol. 13, 972–980 (2012). 3. Zhou, X. et al. Nat. Immunol. 10, 1000–1007 (2009).

4. Cvetanovich, G.L. & Hafler, D.A. Curr. Opin. Immunol. 22, 753–760 (2010). 5. Komatsu, N. et al Nat. Med. 20, 62–68 (2014). 6. Bailey-Bucktrout, S.L. et al. Immunity 39, 949–962 (2013). 7. Edwards, J.R. & Mundy, G.R. Rheumatology 7, 235–243 (2011). 8. Miyao, T. et al. Immunity 36, 262–275 (2012). 9. Ohkura, N. et al. Immunity 37, 785–799 (2012). 10. Williams, L.M. & Rudensky, A.Y. Nat. Immunol. 8, 277–284 (2007). 11. Koch, M.A. et al. Nat. Immunol. 10, 595–602 (2009). 12. Chaudhry, A. et al. Science 326, 986–991 (2009). 13. Bettelli, E. et al. Nature 441, 235–238 (2006). 14. Korn, T. et al. Proc. Natl. Acad. Sci. USA 105, 18460–18465 (2008). 15. Nie, H. et al. Nat. Med. 19, 322–328 (2013). 16. Korn, T. et al. Nat. Med. 13, 423–431 (2007).

Hepatocytes break the silence during liver-stage malaria Ashraful Haque & Christian Engwerda Liver-stage Plasmodium infection triggers a type I interferon transcriptional program in hepatocytes that amplifies an innate immune response within hepatic myeloid cells. This minimizes liver parasite load and delays the release of disease-causing parasites into the bloodstream (pages 47–53). All clinical symptoms of malaria occur in the blood stage of infection; however, parasites transmitted by mosquitoes must first replicate and differentiate for several days in hepatocytes before their release into the bloodstream. Because the liver stage of Plasmodium infection is clinically silent, it has been assumed that this phase does not induce any immunological response, leaving the undetected parasite to multiply with relative impunity. In stark contrast, once parasites invade red blood cells, potent innate and adaptive immune responses are initiated in the spleen1. Recent work suggests that blood-stage parasites are detected by virtue of their AT-rich DNA2— Plasmodium falciparum and the rodent-infective Plasmodia species possess 80% AT-rich genomes—in a manner that triggers a strong type I interferon (IFN) cytokine response. This follows previous studies indicating possible roles for Toll-like receptor (TLR)-mediated detection of parasite-derived molecules, such as hemozoin, a byproduct of hemoglobin catabolism by parasites in red blood cells3,4. However, few, if any, such mechanisms of innate immune sensing have been reported for liver-stage Plasmodium. Thus, the concept Ashraful Haque and Christian Engwerda are at the QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. e-mail: [email protected]

of immunological silence during liver-stage infection has remained unchallenged. In this issue of Nature Medicine, Liehl et al.5 used mouse models of liver-stage Plasmodium infection to argue against this established paradigm. They propose Plasmodium RNA as a new pathogen-associated molecular pattern (PAMP) detected within hepatocytes via the cytosolic pattern recognition receptor MDA5. Transmission of this signal via the adaptor protein MAVS and the transcription factors IRF3 and IRF7 induced type I IFN signaling, first in hepatocytes and then in myeloid cells, which culminated in an innate antiparasitic immune response. To provide evidence of immune responses during liver-stage infection, the authors conducted whole-genome transcriptional analysis on infected and naive livers from mice infected with rodent-infective Plasmodia and found that many upregulated genes were associated with type I IFN responses5. By focusing on a panel of ‘interferon-stimulated genes’ (ISGs), and using mice in which type I IFN signaling was disrupted only in hepatocytes (albuminCre Ifnar1fl/fl mice), they were able to show that this initial type I IFN response was restricted to hepatocytes. Next, infected bone marrow–chimeric mice were used to show that radio-resistant cells, probably hepatocytes, needed IRF3 to drive the type I IFN response. Crucially, using several

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­different mice deficient in myeloid differentiation factor-88, TIR-domain-containing adapter­inducing interferon-β, TLR3 and TLR4, ISG upregulation in the liver was shown to occur independently of all TLR-signaling, but was entirely abrogated in mice lacking the cytosolic sensing adaptor Mavs. The cytosolic sensor Mda5 also played a part in stimulating type I IFN responses in the liver: given its role as a sensor for RNA, Liehl et al.5 transfected macrophages in vitro with Plasmodium RNA species and were able to detect Mda5-dependent ISG gene transcription. Together, these data identify Plasmodium RNA as a candidate PAMP, which is detected by MDA5 and possibly via other sensors that signal through MAVS (Fig. 1). The authors further explored whether type IFN I signaling triggered within hepatocytes is required for host defense by assessing the outcome of liver-stage infection, either in the complete absence of type I IFN signaling or when this signaling was only abrogated in hepatocytes5. In either case, liver parasite burdens increased, demonstrating for the first time that type I IFN–mediated antiparasitic innate immune responses occur during liver-stage Plasmodium infection. Intriguingly, hepatotropic viral co-infection or drug-mediated enhancement of type I IFN responses further improved parasite control in the liver, showing that type I IFN–mediated control of parasites in the liver is suboptimal. Notably, this 17

Good guys gone bad: exTreg cells promote autoimmune arthritis.

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