title: IL-13 production by regulatory T cells protects against experimental autoimmune encephalomyelitis independently of autoantigen.
abstract: Treatment with an anti-inflammatory Salmonella vaccine expressing enterotoxigenic Escherichia coli colonization factor Ag 1 (CFA/I) proved effective in stimulating protective, potent CD25(+)CD4(+) regulatory T (T(reg)) cells in susceptible mice challenged with experimental autoimmune encephalomyelitis (EAE). Because the Salmonella vector was considerably less protective, we questioned whether altering fimbrial subunit expression to resemble conventional Salmonella expression may impact T(reg) cell potency. The Salmonella-CFA/I vaccine was modified to limit fimbrial subunit expression to the intracellular compartment (Salmonella-CFA/I(IC)). SJL mice were challenged with proteolipid protein peptide 139-151 to induce EAE and orally treated with one of three Salmonella vaccines 6 days postchallenge. Treatment with Salmonella-CFA/I(IC) greatly reduced clinical disease, similarly as Salmonella-CFA/I, by subduing IL-17 and IL-21; however, mechanisms of protection differed as evident by increased IL-13 and IFN-gamma but diminished TGF-beta production by T(reg) cells from Salmonella-CFA/I(IC)-treated mice. Adoptive transfer of T(reg) cells from both CFA/I-expressing constructs was equivalent in protecting against EAE, showing minimal disease. Although not as potent in its protection, CD25(-)CD4(+) T cells from Salmonella-CFA/I(IC) showed minimal Th2 cells, but vaccination did prime these Th2 cells rendering partial protection against EAE challenge. In vivo IL-13 but not IFN-gamma neutralization compromised protection conferred by adoptive transfer with Salmonella-CFA/I(IC)-induced T(reg) cells. Thus, the Salmonella-CFA/I(IC) vaccine elicits T(reg) cells with attributes from both the Salmonella vector and Salmonella-CFA/I vaccines. Importantly, these T(reg) cells can be induced to high potency by simply vaccinating against irrelevant Ags, offering a novel approach to treat autoimmune diseases independently of the autoantigen.
authors.affiliation: Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Ochoa-Repáraz
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Rynda
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Ascón
authors.forename: Xinghong
authors.initials: X
authors.lastname: Yang
authors.forename: Irina
authors.initials: I
authors.lastname: Kochetkova
authors.forename: Carol
authors.initials: C
authors.lastname: Riccardi
authors.forename: Gayle
authors.initials: G
authors.lastname: Callis
authors.forename: Theresa
authors.initials: T
authors.lastname: Trunkle
authors.forename: David W
authors.initials: DW
authors.lastname: Pascual
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000276:immunology / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D036781:Fimbriae Proteins / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018793:Interleukin-13 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D022562:Salmonella Vaccines / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D001324:Autoantigens; D016207:Cytokines; D018793:Interleukin-13; D022562:Salmonella Vaccines; C022924:colonization factor antigens; D036781:Fimbriae Proteins; D007371:Interferon-gamma