title: Role of Blimp-1 in programing Th effector cells into IL-10 producers.
abstract: Secretion of the immunosuppressive cytokine interleukin (IL) 10 by effector T cells is an essential mechanism of self-limitation during infection. However, the transcriptional regulation of IL-10 expression in proinflammatory T helper (Th) 1 cells is insufficiently understood. We report a crucial role for the transcriptional regulator Blimp-1, induced by IL-12 in a STAT4-dependent manner, in controlling IL-10 expression in Th1 cells. Blimp-1 deficiency led to excessive inflammation during Toxoplasma gondii infection with increased mortality. IL-10 production from Th1 cells was strictly dependent on Blimp-1 but was further enhanced by the synergistic function of c-Maf, a transcriptional regulator of IL-10 induced by multiple factors, such as the Notch pathway. We found Blimp-1 expression, which was also broadly induced by IL-27 in effector T cells, to be antagonized by transforming growth factor (TGF) β. While effectively blocking IL-10 production from Th1 cells, TGF-β shifted IL-10 regulation from a Blimp-1-dependent to a Blimp-1-independent pathway in IL-27-induced Tr1 (T regulatory 1) cells. Our findings further illustrate how IL-10 regulation in Th cells relies on several transcriptional programs that integrate various signals from the environment to fine-tune expression of this critical immunosuppressive cytokine.
authors: German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany Department of Rheumatology and Clinical Immunology, Medical Clinic I, Gastroenterology, and Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany.
authors: Christian
authors: C
authors: Neumann
authors: German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany.
authors: Frederik
authors: F
authors: Heinrich
authors: German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany Department of Rheumatology and Clinical Immunology, Medical Clinic I, Gastroenterology, and Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany.
authors: Katrin
authors: K
authors: Neumann
authors: German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany Department of Rheumatology and Clinical Immunology, Medical Clinic I, Gastroenterology, and Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany.
authors: Victoria
authors: V
authors: Junghans
authors: German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany.
authors: Mir-Farzin
authors: MF
authors: Mashreghi
authors: German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany Department of Rheumatology and Clinical Immunology, Medical Clinic I, Gastroenterology, and Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany.
authors: Jonas
authors: J
authors: Ahlers
authors: German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany.
authors: Marko
authors: M
authors: Janke
authors: German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany Department of Rheumatology and Clinical Immunology, Medical Clinic I, Gastroenterology, and Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany.
authors: Christine
authors: C
authors: Rudolph
authors: Miltenyi Biotec GmbH, 51429 Bergisch Gladbach, Germany.
authors: Nadine
authors: N
authors: Mockel-Tenbrinck
authors: Department of Rheumatology and Clinical Immunology, Medical Clinic I, Gastroenterology, and Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany.
authors: Anja A
authors: AA
authors: Kühl
authors: Department of Rheumatology and Clinical Immunology, Medical Clinic I, Gastroenterology, and Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany.
authors: Markus M
authors: MM
authors: Heimesaat
authors: Leibniz Research Institute for Environmental Medicine, 40225 Düsseldorf, Germany.
authors: Charlotte
authors: C
authors: Esser
authors: Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS) Pohang, Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, Republic of Korea.
authors: Sin-Hyeog
authors: SH
authors: Im
authors: German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany.
authors: Andreas
authors: A
authors: Radbruch
authors: German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany alexander.scheffold@charite.de saschar@gene.com.
authors: Sascha
authors: S
authors: Rutz
authors: German Rheumatism Research Centre Berlin, an Institute of the Leibniz-Association, 10117 Berlin, Germany Department of Rheumatology and Clinical Immunology, Medical Clinic I, Gastroenterology, and Department of Microbiology and Hygiene, Charité University Hospital, 10117 Berlin, Germany alexander.scheffold@charite.de saschar@gene.com.
authors: Alexander
authors: A
authors: Scheffold
mesh_terms: D000818:Animals; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D018664:Interleukin-12 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051257:Proto-Oncogene Proteins c-maf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D051880:Receptors, Notch / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism*; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C556062:IL10 protein, mouse; C486767:Il27 protein, mouse; D007378:Interleukins; C495608:Maf protein, mouse; C513258:Prdm1 protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D051880:Receptors, Notch; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D000074462:Positive Regulatory Domain I-Binding Factor 1