IL-13 Production by Regulatory T Cells Protects Against Experimental Autoimmune Encephalomyelitis (EAE) Independent of Auto-Antigen

Treatment with an anti-inflammatory Salmonella vaccine expressing enterotoxigenic E. coli colonization factor antigen 1 (CFA/I) proved effective in stimulating protective, potent CD25 + CD4 + T (T reg ) cells in susceptible mice challenged with experimental autoimmune encephalomyelitis (EAE). Since the Salmonella vector was considerably less protective, we questioned whether altering the fimbrial subunit expression to resemble conventional Salmonella expression may impact T reg cell potency. The Salmonella -CFA/I vaccine was modified to limit the fimbrial subunit expression to the intracellular compartment ( Salmonella -CFA/I IC ). SJL mice were challenged with proteolipid protein (PLP) 139–151 to induce EAE and orally treated with one of three Salmonella vaccines six days post-challenge. Treatment with Salmonella -CFA/I IC greatly reduced clinical disease, similar to Salmonella -CFA/I, by subduing IL-17 and IL-21; however, mechanisms of protection differed, as evident by increased IL-13 and IFN-γ, but diminished TGF-β 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. While not as potent in its protection, CD25 − CD4 + T cells from Salmonella -CFA/I IC showed minimal Th2 cells, but this vaccine did prime for Th2 cells subsequent EAE challenge. In vivo IL-13, but not IFN-γ 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 auto-Ag.