title: TGF-β signaling via Smad4 drives IL-10 production in effector Th1 cells and reduces T-cell trafficking in EAE.
abstract: Effector Th1 cells perpetuate inflammatory damage in a number of autoimmune diseases, including MS and its animal model EAE. Recently, a self-regulatory mechanism was described in which effector Th1 cells produce the immunomodulatory cytokine IL-10 to dampen the inflammatory response in both normal and autoimmune inflammation. While the presence of TGF-β has been suggested to enhance and stabilize an IFN-γ(+) IL-10(+)  phenotype, the molecular mechanism is poorly understood. Additionally, in the context of adoptive transfer EAE, it is unclear whether IL-10 acts on the transferred Th1 cells or on endogenous host cells. In the present study, using myelin-specific TCR-Tg mice, we show that repetitive Ag stimulation of effector Th1 cells in the presence of TGF-β increases the population of IFN-γ(+) IL-10(+)  cells, which correlates with a decrease in EAE severity. Additionally, TGF-β signaling causes binding of Smad4 to the IL-10 promoter, providing molecular evidence for TGF-β-mediated IL-10 production from Th1 effector cells. Finally, this study demonstrates that IL-10 not only reduces encephalitogenic markers such as IFN-γ and T-bet on Th1 effector cells expressing the IL-10R but also prevents recruitment of both transferred and host-derived inflammatory T cells. These data establish a regulatory mechanism by which highly activated Th1 effector cells modulate their pathogenicity through the induction of IL-10.
authors: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Medical Center, Columbus, OH, USA.
authors: David J
authors: DJ
authors: Huss
authors: Ryan C
authors: RC
authors: Winger
authors: Gina Mavrikis
authors: GM
authors: Cox
authors: Mireia
authors: M
authors: Guerau-de-Arellano
authors: Yuhong
authors: Y
authors: Yang
authors: Michael K
authors: MK
authors: Racke
authors: Amy E
authors: AE
authors: Lovett-Racke
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D020381:Interleukin-17 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000276:immunology; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000096:biosynthesis; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma