title: IL-21R signaling is critical for induction of spontaneous experimental autoimmune encephalomyelitis.
abstract: IL-17-producing CD4+ T cells (Th17 cells) have well-described pathogenic roles in tissue inflammation and autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE); however, the involvement of IL-21 in these processes has remained controversial. While IL-21 is an essential autocrine amplification factor for differentiation of Th17 cells, the loss of IL-21 or IL-21 receptor (IL-21R) does not protect mice from actively induced EAE. Here, we utilized a transgenic EAE mouse model, in which T and B cells overexpress receptors for myelin oligodendrocyte glycoprotein (MOG) (referred to as 2D2xTH mice), and demonstrated that IL-21 is critical for the development of a variant form of spontaneous EAE in these animals. Il21r deletion in 2D2xTH mice reduced the incidence and severity of spontaneous EAE, which was associated with a defect in Th17 cell generation. Moreover, IL-21R deficiency limited IL-23R expression on Th17 cells and inhibited expression of key molecules involved in the generation of pathogenic Th17 cells. Conversely, loss of IL-23R in 2D2xTH mice resulted in complete resistance to the development of spontaneous EAE. Our data identify a previously unappreciated role for IL-21 in EAE and reveal that IL-21-mediated signaling supports generation and stabilization of pathogenic Th17 cells and development of spontaneous autoimmunity.
authors.forename: Youjin
authors.initials: Y
authors.lastname: Lee
authors.forename: Meike
authors.initials: M
authors.lastname: Mitsdoerffer
authors.forename: Sheng
authors.initials: S
authors.lastname: Xiao
authors.forename: Guangxiang
authors.initials: G
authors.lastname: Gu
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D002478:Cells, Cultured; D004198:Disease Susceptibility; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D053738:Interleukin-21 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007378:Interleukins / Q000502:physiology*; D008213:Lymphocyte Activation; D038041:Lymphopoiesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D058504:Th17 Cells / Q000276:immunology*; D000098546:Interleukin-21
chemical_list: C508118:Il21r protein, mouse; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D018123:Receptors, Interleukin; C528688:interleukin-23 receptor, mouse; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma; D000098546:Interleukin-21