title: The NF-κB transcription factor c-Rel is required for Th17 effector cell development in experimental autoimmune encephalomyelitis.
abstract: Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated autoimmune disease involving effector Th subsets such as Th1 and Th17. In this study, we demonstrate that mice lacking the NF-κB transcription factor family member c-Rel (rel(-/-)), which are known to be resistant to EAE, show impaired Th17 development. Mixed bone marrow chimeras and EAE adoptive transfer experiments show that the deficiency of effector Th17 cells in rel(-/-) mice is T cell intrinsic. Consistent with this finding, c-Rel was activated in response to TCR signaling in the early stages of Th17 development and controlled the expression of Rorc, which encodes the Th17 transcription factor retinoic acid-related orphan receptor γt. CD28, but not IL-2, repression of Th17 development was dependent on c-Rel, implicating a dual role for c-Rel in modulating Th17 development. Adoptive transfer experiments also suggested that c-Rel control of regulatory T cell differentiation and homeostasis influences EAE development and severity by influencing the balance between Th17 and regulatory T cells. Collectively, our findings indicate that in addition to promoting Th1 differentiation, c-Rel regulates the development and severity of EAE via multiple mechanisms that impact on the generation of Th17 cells.
authors.affiliation: Gene Expression and Epigenomics Laboratory, Department of Genome Biology, The John Curtin School of Medical Research, Australian National University, Canberra 2600, Australia.
authors.forename: Guobing
authors.initials: G
authors.lastname: Chen
authors.forename: Kristine
authors.initials: K
authors.lastname: Hardy
authors.forename: Eloisa
authors.initials: E
authors.lastname: Pagler
authors.forename: Lina
authors.initials: L
authors.lastname: Ma
authors.forename: Seungsoo
authors.initials: S
authors.lastname: Lee
authors.forename: Steve
authors.initials: S
authors.lastname: Gerondakis
authors.forename: Stephen
authors.initials: S
authors.lastname: Daley
authors.forename: M Frances
authors.initials: MF
authors.lastname: Shannon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018106:CD28 Antigens / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020569:Proto-Oncogene Proteins c-rel / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology* / Q000473:pathology
chemical_list: D018106:CD28 Antigens; D006131:Growth Inhibitors; D020569:Proto-Oncogene Proteins c-rel