title: TGF-β signaling initiated in dendritic cells instructs suppressive effects on Th17 differentiation at the site of neuroinflammation.
abstract: While the role of Transforming Growth Factor β (TGF-β) as an intrinsic pathway has been well established in driving de novo differentiation of Th17 cells, no study has directly assessed the capacity of TGF-β signaling initiated within dendritic cells (DCs) to regulate Th17 differentiation. The central finding of this study is the demonstration that Th17 cell fate during autoimmune inflammation is shaped by TGF-β extrinsic pathway via DCs. First, we provide evidence that TGF-β limits at the site of inflammation the differentiation of highly mature DCs as a means of restricting Th17 cell differentiation and controlling autoimmunity. Second, we demonstrate that TGF-β controls DC differentiation in the inflammatory site but not in the priming site. Third, we show that TGF-β controls DC numbers at a precursor level but not at a mature stage. While it is undisputable that TGF-β intrinsic pathway drives Th17 differentiation, our data provide the first evidence that TGF-β can restrict Th17 differentiation via DC suppression but such a control occurs in the site of inflammation, not at the site of priming. Such a demarcation of the role of TGF-β in DC lineage is unprecedented and holds serious implications vis-à-vis future DC-based therapeutic targets.
authors: Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.
authors: Suzanne
authors: S
authors: Speck
authors: Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.
authors: James
authors: J
authors: Lim
authors: Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.
authors: Sagar
authors: S
authors: Shelake
authors: Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.
authors: Marsel
authors: M
authors: Matka
authors: Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.
authors: Jonathan
authors: J
authors: Stoddard
authors: Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.
authors: Alexander
authors: A
authors: Farr
authors: Evegrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors: Vijay
authors: V
authors: Kuchroo
authors: Department of Microbiology and Immunology, University of Michigan School of Medicine, Ann Arbor, Michigan, United States of America.
authors: Yasmina
authors: Y
authors: Laouar
mesh_terms: D000818:Animals; D039521:CD11c Antigen; D002452:Cell Count; D002454:Cell Differentiation; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000175:diagnosis / Q000276:immunology / Q000378:metabolism; D051379:Mice; D057054:Molecular Imaging; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D039521:CD11c Antigen; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta