AtRA restores the stability and functionality of nTregs in the inflammatory milieu (96.17)

Abstract

Abstract Natural Tregs play an important role in the maintenance of immune tolerance. Recent studies revealed that nTregs are plastic and unstable when stimulated with IL-6. They can be converted into either Th1, or Th17 or Th2 cells and lose phenotypic and functional characteristics in inflammatory milieu. all-trans Retinoic Acid (atRA) not only promotes Foxp3+ cell development, but restrains Th17 cell differentiation induced by IL-6+TGF-β. We here report that addition of atRA blocked Th17 conversion from nTregs. atRA-nTregs expressed lower levels of CD126 (IL-6Rα chain) and phosphorylated STAT3 compared to DMSO-nTregs when stimulated with IL-6. atRA- but not DMSO-nTregs maintained the suppressive activity in the presence of IL-6. Adoptive transfer of atRA- but not DMSO-pretreated nTregs to DBA/1 mice at day 28 after immunization with CII/CFA significantly reduced the severity of CIA. Using CFSE-labeled donor cells, we were able to observe that majority of nTreg cells lost Foxp3 expression, converted to IL-17-prodcuing cells, and >20% converted into Th2 cells in draining lymph nodes at one week after adoptive transfer to the established CIA. Conversely, atRA-nTregs maintained Foxp3 expression and did not convert to Th1, Th2 and Th17 cells in CIA. atRA alters Treg plasticity and restores the functionality of nTregs in the inflammatory milieu. This study may provide a novel therapeutic approach of nTregs for the treatment of Rheumatoid Arthritis and other autoimmune diseases.