title: Oral Escherichia coli colonization factor antigen I fimbriae ameliorate arthritis via IL-35, not IL-27.
abstract: A Salmonella therapeutic expressing enterotoxigenic Escherichia coli colonization factor Ag I (CFA/I) fimbriae protects against collagen-induced arthritis (CIA) by eliciting two regulatory T cell (Treg) subsets: TGF-β-producing Foxp3(-)CD39(+)CD4(+) T cells and IL-10-producing Foxp3(+)CD39(+)CD4(+) T cells. However, it is unclear whether CFA/I fimbriae alone are protective and whether other regulatory cytokines are involved, especially in the context for the EBI3-sharing cytokines, Treg-derived IL-35 and APC-derived IL-27, both capable of suppressing Th17 cells and regulating autoimmune diseases. Subsequent evaluation revealed that a single oral dose of purified, soluble CFA/I fimbriae protected against CIA as effectively as did Salmonella-CFA/I and found that Foxp3(+)CD39(+)CD4(+) T cells were the source of secreted IL-35, whereas IL-27 production by CD11c(+) cells was inhibited. Inquiring into their relevance, CFA/I fimbriae-treated IL-27R-deficient (WSX-1(-/-)) mice were equally protected against CIA as were wild-type mice, suggesting a limited role for IL-27. In contrast, CFA/I fimbriae-mediated protection was abated in EBI3(-/-) mice, accompanied by the loss of TGF-β- and IL-10-producing Tregs. Adoptive transfer of C57BL/6 CD39(+)CD4(+) T cells to EBI3(-/-) mice with concurrent CFA/I plus IL-35 treatment effectively stimulated Tregs suppressing proinflammatory collagen II-specific Th cells. In contrast, recipients cotransferred with C57BL/6 and EBI3(-/-) CD39(+)CD4(+) T cells and treated with CFA/I plus IL-35 were not protected, implicating the importance of endogenous IL-35 for conferring CFA/I-mediated protection. Thus, CFA/I fimbriae stimulate IL-35 required for the coinduction of TGF-β and IL-10.
authors: Department of Immunology and Infectious Diseases, Montana State University, Bozeman, MT 59717.
authors: Irina
authors: I
authors: Kochetkova
authors: Theresa
authors: T
authors: Thornburg
authors: Gayle
authors: G
authors: Callis
authors: Kathryn
authors: K
authors: Holderness
authors: Massimo
authors: M
authors: Maddaloni
authors: David W
authors: DW
authors: Pascual
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology*; D036781:Fimbriae Proteins / Q000276:immunology*; D010861:Fimbriae, Bacterial / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D064094:Interleukin-27 / Q000276:immunology*; D007378:Interleukins / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D015703:Antigens, CD; C499601:Ebi3 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D064094:Interleukin-27; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; D016212:Transforming Growth Factor beta; C022924:colonization factor antigens; C569375:interleukin-35, mouse; D016753:Interleukin-10; D036781:Fimbriae Proteins