All-trans Retinoic Acid Inhibits Type 1 Diabetes by T Regulatory (Treg)-Dependent Suppression of Interferon-γ–Producing T-cells Without Affecting Th17 Cells

OBJECTIVE—All-trans retinoic acid (ATRA), a potent derivative of vitamin A, can regulate immune responses. However, its role in inducing immune tolerance associated with the prevention of islet inflammation and inhibition of type 1 diabetes remains unclear. RESEARCH DESIGN AND METHODS—We investigated the mechanisms underlying the potential immunoregulatory effect of ATRA on type 1 diabetes using an adoptive transfer animal model of the disease. RESULTS—Our data demonstrated that ATRA treatment inhibited diabetes in NOD mice with established insulitis. In addition, it suppressed interferon (IFN)-γ–producing CD4(+) and CD8(+) T effector (Teff) cells and expanded T regulatory (Treg) cells in recipient mice transferred with diabetic NOD splenocytes, without affecting either interleukin (IL)-17 –or IL-4–producing cells. Consistent with these results, ATRA reduced T-bet and STAT4 expression in T-cells and decreased islet-infiltrating CD8(+) T-cells, suppressing their activation and IFN-γ/granzyme B expression. Depletion of CD4(+)CD25(+) Treg cells impaired the inhibitory effect of ATRA on islet-infiltrating T-cells and blocked its protective effect on diabetes. Therefore, ATRA treatment induced Treg cell–dependent immune tolerance by suppressing both CD4(+) and CD8(+) Teff cells while promoting Treg cell expansion. CONCLUSIONS—These results demonstrate that ATRA treatment promoted in vivo expansion of Treg cells and induced Treg cell–dependent immune tolerance by suppressing IFN-γ–producing T-cells, without affecting Th17 cells. Our study also provides novel insights into how ATRA induces immune tolerance in vivo via its effects on Teff and Treg cells.