PPARgamma regulates retinoic acid-mediated DC induction of Tregs

CD4+ CD25+ Foxp3+ Tregs are critical regulators of immune responses and autoimmune diseases. nTregs are thymically derived; iTregs are converted in the periphery from CD4+ CD25- Foxp3- Teffs. Recent studies reported that GALT CD103+ DCs mediated enhanced iTreg conversion via the secretion of RA. However, the factors regulating RA secretion and hence, the induction of iTregs by DCs are not yet clear. Activation of the nuclear hormone receptor PPARgamma has been shown to induce RA expression in human DCs, and thus, we postulated that PPARgamma activation in DCs may be an important regulator of RA secretion and iTreg generation. Using in vitro and in vivo approaches, we now demonstrate that PPARgamma activation enhances iTreg generation through increased RA synthesis from murine splenic DCs. In addition, we demonstrate that inhibition of DC PPARgamma decreases iTreg generation, suggesting a role for endogenous PPARgamma ligands in this process. Overall, our findings suggest that PPARgamma may be important as a factor that stimulates DCs to produce RA and as a potential mechanism by which PPARgamma ligands ameliorate autoimmunity.