Critical role of all-trans retinoic acid in stabilizing human nTregs under inflammatory conditions (P5133)

Abstract Recent studies have demonstrated that thymus-derived naturally-occurring CD4+Foxp3+ regulatory T cells (nTregs) in both human and mouse are unstable and dysfunctional in the presence of pro-inflammatory cytokines. All-trans Retinoic Acid (atRA), the active derivative of vitamin A, has been shown to regulate Treg and T effector cell differentiation. Herein, we report that atRA prevents human nTregs from converting to Th1 and/or Th17 cells and sustains their Foxp3 expression and suppressive function in vitro or in vivo following encountering with IL-1 and IL-6. Interestingly, adoptive transfer of human nTregs pre-treated with atRA significantly enhanced their suppressive effect on xeno-graft versus host diseases (xGVHD) and only these cells after stimulating with IL-1/IL-6 sustained the functional activity against xGVHD in a humanized animal model. atRA suppresses IL-1R upregulation and accelerates IL-6R downregulation and diminishes their signaling events, as well as increases histone acetylation on FOXP3 gene promoter and CpG demethylation in CNS regions of FOXP3 gene locus. These results strongly implicate that nTregs primed with atRA may represent a novel treatment strategy to control established chronic immune-mediated inflammatory diseases.