IL-13 production by regulatory T cells protects against experimental autoimmune encephalomyelitis independently of autoantigen

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-γbut diminished TGF-βproduction 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-γneutralization 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.