TY - JOUR
T1 - IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1
AU - Heinemann, Christina
AU - Heink, Sylvia
AU - Petermann, Franziska
AU - Vasanthakumar, Ajithkumar
AU - Rothhammer, Veit
AU - Doorduijn, Elien
AU - Mitsdoerffer, Meike
AU - Sie, Christopher
AU - Da Costa, Olivia Prazeres
AU - Buch, Thorsten
AU - Hemmer, Bernhard
AU - Oukka, Mohamed
AU - Kallies, Axel
AU - Korn, Thomas
N1 - Funding Information:
We would like to thank Reinhard Obst for helping with microarray data analysis, and Malte Claussen for helping with initial experiments, as well as Svenja Woeste and Veronika Husterer for skilful technical assistance. S.H. was supported by the Gemein-nützige Hertie Stiftung. M.M. received intramural funding by the Klinikum rechts der Isar (KKF). C.S. holds a PHD fellowship from Boehringer Ingelheim Fonds. A.K. was supported by grants and fellowships from the National Health and Medical Research Council of Australia, the Australian Research Council and the Sylvia and Charles Viertel Foundation. This study was partially made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support scheme. T.K. is the recipient of a Heisenberg award by the Deutsche Forschungsgemeinschaft (DFG, KO2964/3-2). This work was supported by the DFG (SFB1054/B06, TR128/A06, A07).
PY - 2014/5/6
Y1 - 2014/5/6
N2 - Central nervous system (CNS) autoimmunity is regulated by the balance of pro-inflammatory cytokines and IL-10. Here we identify the transcriptional regulator Blimp1 as crucial to induce IL-10 in inflammatory T helper cells. Pre-committed Th17 cells respond to IL-27 and IL-12 by upregulating Blimp1 and adopt a Tr-1-like phenotype characterized by IL-10 and IFN-Î 3 production. Accordingly, Blimp1-deficient effector T cells fail to produce IL-10, and deficiency in Tr-1 cell function leads to uncontrolled Th17 cell-driven CNS pathology without the need to stabilize the Th17 phenotype with IL-23. IL-23 counteracts IL-27 and IL-12-mediated effects on Tr-1-development reinforcing the pro-inflammatory phenotype of Th17 cells. Thus, the balance of IL-23 vs IL-12/IL-27 signals into CD4+ effector T cells determines whether tissue inflammation is perpetuated or resolves.
AB - Central nervous system (CNS) autoimmunity is regulated by the balance of pro-inflammatory cytokines and IL-10. Here we identify the transcriptional regulator Blimp1 as crucial to induce IL-10 in inflammatory T helper cells. Pre-committed Th17 cells respond to IL-27 and IL-12 by upregulating Blimp1 and adopt a Tr-1-like phenotype characterized by IL-10 and IFN-Î 3 production. Accordingly, Blimp1-deficient effector T cells fail to produce IL-10, and deficiency in Tr-1 cell function leads to uncontrolled Th17 cell-driven CNS pathology without the need to stabilize the Th17 phenotype with IL-23. IL-23 counteracts IL-27 and IL-12-mediated effects on Tr-1-development reinforcing the pro-inflammatory phenotype of Th17 cells. Thus, the balance of IL-23 vs IL-12/IL-27 signals into CD4+ effector T cells determines whether tissue inflammation is perpetuated or resolves.
UR - https://www.scopus.com/pages/publications/84900028407
U2 - 10.1038/ncomms4770
DO - 10.1038/ncomms4770
M3 - Article
C2 - 24796719
AN - SCOPUS:84900028407
SN - 2041-1723
VL - 5
JO - Nature Communications
JF - Nature Communications
M1 - 3770
ER -