1054 VOLUME 14 NUMBER 10 OCTOBER 2013 NATURE IMMUNOLOGY ARTICLES The dysregulated activity of effector cells of the T H 1 and T H 17 subsets of helper T cells results in the development of tissue inflammation and autoimmunity. Myelin-specific T H 1 and T H 17 cells, for example, contribute to disease pathogenesis in multiple sclerosis (MS) 1 and its animal model, experimental autoimmune encephalomyelitis (EAE) 2 . During EAE, dendritic cells (DCs) control the activation and differen- tiation of myelin-specific effector T cells and regulatory T cells (T reg cells) 3,4 . Moreover, DCs isolated from patients with MS produce large amounts of T H 1- and T H 17-polarizing cytokines 5 , which suggests that DCs promote the generation of the pathogenic T cell response in MS. Indeed, DCs control several pathogenic mechanisms associated with the development of central nervous system (CNS) autoimmunity. DCs promote the entry of T cells into the CNS 6 , the activation and differentiation of pathogenic T cells in the CNS 3 and the spreading of the autoimmune response to new CNS epitopes 7 . Thus, it is important to study the pathways that regulate DC activity during the course of autoimmunity, to identify mechanisms of disease pathogenesis and also to develop new approaches for therapeutic intervention. IL-27 is a cytokine structurally related to IL-12 and is composed of a p28 subunit and the product of Epstein-Barr virus–induced gene 3 (Ebi3) 8 . IL-27 signals through a receptor composed of the common IL-6 receptor chain gp130 (which is used by several other members of the IL-6 and IL-12 families) and a unique IL-27 receptor α-chain (IL-27RA) that is homologous to the IL-12Rβ2 chain of the IL-12 receptor 8 . IL-27 is produced by DCs in response to activation via Toll-like receptors through a mechanism that involves the autocrine effects of interferon-β (IFN-β) 9 . Indeed, the therapeutic effects of IFN-β administration on relapsing-remitting MS have been linked to the induction of IL-27 production by DCs 10 . On the basis of its structural homology to IL-12 and its ability to trigger IFN-γ production, IL-27 was initially thought to be a proin- flammatory cytokine 11 . However, it was subsequently discovered that IL-27 suppresses T H 1, T H 2 and T H 17 responses and limits CNS inflammation in several experimental models 8 . In the EAE model, the administration of IL-27 inhibits disease development 12 . Conversely, the lack of a functional IL-27 receptor results in exacerbated T H 17 responses and the worsening of EAE 12,13 . IL-27 acts directly on T cells to inhibit the development of pathogenic T H 17 cells and to promote the differentiation of IL-10-producing type 1 T reg cells (Tr1 cells) 12–17 . Thus, the arrest of EAE by IL-27 is thought to reflect its direct effects on T cells. However, several cell types beyond T cells express the IL-27 receptor, but the relevance of IL-27 signaling in those cells for the control of EAE and autoimmunity is unknown. DCs express a functional IL-27 receptor 18 ; however, although IL-27 has been reported to interfere with the activation of DCs in vitro 18–20 , the physiological relevance of IL-27 signaling in DCs and its effects on the control of the T cell response and autoimmunity are unknown. In this work, we studied the effects of IL-27 signaling in DCs on the dif- ferentiation of effector T cells and T reg cells and CNS autoimmunity. We found that IL-27 signaling in DCs upregulated expression of the immunoregulatory molecule CD39 (encoded by Entpd1) and lim- ited the development of EAE. CD39 expressed by conventional DCs (cDCs) reduced the extracellular concentration of ATP and decreased ATP-triggered activation of the NLRP3 inflammasome. Moreover, we 1 Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 2 The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel. 3 Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA. 4 These authors contributed equally to this work. Correspondence should be addressed to F.J.Q. (fquintana@rics.bwh.harvard.edu). Received 18 March; accepted 19 July; published online 1 September 2013; doi:10.1038/ni.2695 IL-27 acts on DCs to suppress the T cell response and autoimmunity by inducing expression of the immunoregulatory molecule CD39 Ivan D Mascanfroni 1,4 , Ada Yeste 1,4 , Silvio M Vieira 1 , Evan J Burns 1 , Bonny Patel 1 , Ido Sloma 2 , Yan Wu 3 , Lior Mayo 1 , Rotem Ben-Hamo 2 , Sol Efroni 2 , Vijay K Kuchroo 1 , Simon C Robson 3 & Francisco J Quintana 1 Dendritic cells (DCs) control the balance between effector T cells and regulatory T cells in vivo. Hence, the study of DCs might identify mechanisms of disease pathogenesis and guide new therapeutic approaches for disorders mediated by the immune system. We found that interleukin 27 (IL-27) signaling in mouse DCs limited the generation of effector cells of the T H 1 and T H 17 subsets of helper T cells and the development of experimental autoimmune encephalomyelitis (EAE). The effects of IL-27 were mediated at least in part through induction of the immunoregulatory molecule CD39 in DCs. IL-27-induced CD39 decreased the extracellular concentration of ATP and downregulated nucleotide-dependent activation of the NLRP3 inflammasome. Finally, therapeutic vaccination with IL-27-conditioned DCs suppressed established relapsing-remitting EAE. Thus, IL-27 signaling in DCs limited pathogenic T cell responses and the development of autoimmunity. npg © 2013 Nature America, Inc. All rights reserved.