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* Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717; and
Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205
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 (Treg) 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 Treg cell potency. The Salmonella-CFA/I vaccine was modified to limit fimbrial subunit expression to the intracellular compartment (Salmonella-CFA/IIC). 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/IIC 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-
but diminished TGF-β production by Treg cells from Salmonella-CFA/IIC-treated mice. Adoptive transfer of Treg 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/IIC showed minimal Th2 cells, but vaccination did prime these Th2 cells rendering partial protection against EAE challenge. In vivo IL-13 but not IFN- neutralization compromised protection conferred by adoptive transfer with Salmonella-CFA/IIC-induced Treg cells. Thus, the Salmonella-CFA/IIC vaccine elicits Treg cells with attributes from both the Salmonella vector and Salmonella-CFA/I vaccines. Importantly, these Treg 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Public Health Service Grant AI-41123 and, in part, by Montana Agricultural Station and U.S. Department of Agriculture Formula Funds. The Veterninary Molecular Biology flow cytometry facility was, in part, supported by National Institutes of Health/National Center for Research Resources, Centers of Biomedical Excellence Grant P20 RR-020185 and by an equipment grant from the M. J. Murdock Charitable Trust.
2 Current address: Department of Microbiology and Immunology, Dartmouth Medical School, HB 7937, Dartmouth-Hitchcock Medical Center, Rubin Building, Room 710, 1 Medical Center Drive, Lebanon, NH 03756.
3 Address correspondence and reprint requests to Dr. David W. Pascual, Veterinary Molecular Biology, P. O. Box 173610, Montana State University, Bozeman, MT 59717. E-mail address: dpascual{at}montana.edu
4 Abbreviations used in this paper: CFA/I, colonization factor antigen I; CFA/IIC, CFA/I expressed in the periplasmic/intracellular compartment; EAE, experimental autoimmune encephalomyelitis; GITR, glucocorticoid-induced TNFR; HNLN, head and neck lymph node; LN, lymph node; MLN, mesenteric lymph node; MS, multiple sclerosis; NRS, normal rabbit serum; PLP, protein proteolipid; RANKL, receptor activator of NF-
B ligand; Treg, regulatory T cell.
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