Enterotoxigenic E. coli CFA/I Fimbriae Abate Collagen-Induced Arthritis (CIA) via Regulatory CD39+ T Cells and IL-35 (47.1)

Abstract

Abstract Colonization factor antigen I (CFA/I) expressed by Salmonella vaccine vectors can prevent experimental autoimmune encephalomyelitis and CIA attributed to suppression of Th1 and Th17 cells by regulatory and immune deviation mechanisms. We hypothesize that soluble CFA/I fimbriae may confer similar protection against CIA as Salmonella-CFA/I. Single dose, mucosal CFA/I application 14 days post-CIA induction abated clinical development of arthritis similar to Salmonella-CFA/I. IFN-γ, IL-6, and IL-17 responses by CD4+ T cells were suppressed in protected mice via the induction of IL-10 and regulatory FoxP3+ CD4+ T cells. Such regulatory T cells were both CD25- and CD25+, each conferring protection upon adoptive transfer to CIA mice. Further evaluation revealed the protective CD25- CD4+ T cells also expressed CD39, ectonucleoside triphosphate diphosphohydrolase, an enzyme responsible for extracellular ATP hyrolysis. Flow cytometry analysis revealed that CFA/I fimbriae nearly doubled the CD39+ CD4+ T cell subset, ~50% of which were CD25-negative. Moreover, mucosal CFA/I delivery enhanced by 2-fold IL-35+ FoxP3+ CD4+ regulatory T cells. CD39+ CD4+ T cells accounted for most (~70%) of TGF-β production by CD4+ T cells. Upon restimulation, these CFA/I -induced CD4+ T cells did not produce IFN-γ or IL-17, but IL-10 levels were enhanced. In conclusion, CFA/I fimbriae alone can augment regulatory T cells for protection against autoimmune diseases. Work supported by P01 AT-04986.