TGF-β-induced CD4+ regulatory T cells but not nTregs ameliorate autoimmune arthritis by shifting the balance between Tregs and Th17 cells In vivo (179.14)

Abstract

Abstract Transferred CD4+CD25+Foxp3+ regulatory cells (Tregs) can prevent autoimmune disease, but generally fail to ameliorate established disease. Here we demonstrate that antigen-specific Tregs induced with IL-2 and TGF-β ex-vivo (iTregs), but not equivalent expanded thymus-derived nTregs can prevent progression of established collagen-induced arthritis. This was because following transfer, nTregs exhibited decreased Foxp3 and Bcl-2 expression, decreased suppressive activity, and many converted to Th17 cells. By contrast, transferred iTregs were more numerous, retained their suppressive activity in the presence of IL-6 and were resistant to conversion. Remarkably, ten days after transfer iTregs shifted the predominance from Th17 to Treg cells in draining LNs. These findings provide evidence that transferred TGF-β-induced iTregs are more stable and functional than nTregs in mice with established autoimmunity. Moreover, iTregs can have tolerogenic effects even in the presence of ongoing inflammation. The therapeutic potential of iTregs in subjects with chronic, immune-mediated inflammatory diseases deserves to be investigated.