Dendritic cell tolerogenicity: a key mechanism in immunomodulation by vitamin D receptor agonists

Dendritic cells (DC) induce or tolerize T cells, and tolerogenic DCs can promote the development of regulatory T cells (Treg) with suppressive activity. Thus, the possibility of manipulating DCs and enhancing their tolerogenic properties using different pharmacologic or biologic agents could be exploited to control a variety of chronic immuno-mediated inflammatory conditions. Among agents able to promote induction of tolerogenic DCs, vitamin D receptor (VDR) agonists have attracted considerable attention, also because of their potential in clinical translation. DCs are key targets for the immunomodulatory effects of VDR agonists, which shape DC phenotype and function, enhancing their tolerogenicity in adaptive immune responses. Tolerogenic DCs induced by a short treatment with VDR agonists promote CD4⁺CD25⁺Foxp3⁺ Treg cells that are able to mediate transplantation tolerance and to arrest the development of autoimmune diseases. VDR agonists not only favor induction of CD4⁺CD25⁺ Treg cells, but can also enhance their recruitment at inflammatory sites. The tolerogenic properties induced by VDR agonists in DCs, leading to enhanced Treg cell development, likely contribute to the beneficial activity of these hormone-like molecules in autoimmune disease and graft rejection models, highlighting their applicability to the treatment of chronic inflammatory conditions sustained by autoreactive or alloreactive immune responses.