Abstract

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 IFN-γ-producing CD4⁺ and CD8⁺ T effector (Teff) cells and expanded Treg cells in recipient mice transferred with diabetic NOD splenocytes, without affecting either 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 affects on Teff and Treg cells.