Role of dendritic cells in the induction of regulatory T cells

Abstract

Dendritic cells (DCs) play a key role in initiating immune responses and maintaining immune tolerance. In addition to playing a role in thymic selection, DCs play an active role in tolerance under steady state conditions through several mechanisms which are dependent on IL-10, TGF-β, retinoic acid, indoleamine-2,3,-dioxygenase along with vitamin D. Several of these mechanisms are employed by DCs in induction of regulatory T cells which are comprised of Tr1 regulatory T cells, natural and inducible foxp3+ regulatory T cells, Th3 regulatory T cells and double negative regulatory T cells. It appears that certain DC subsets are highly specialized in inducing regulatory T cell differentiation and in some tissues the local microenvironment plays a role in driving DCs towards a tolerogenic response. In this review we discuss the recent advances in our understanding of the mechanisms underlying DC driven regulatory T cell induction.

Figure 1

DCs drive differentiation of Tr1 regulatory T cells. DCs secrete IL-27, IL-10 and TGF-β1, which induce AhR and c-maf in T cells. AhR and c-maf physically associate with each other and activate IL-10 and IL-21 promoters, driving Tr1 differentiation. IL-27 suppresses production of Th17 inducing cytokines such as IL-1β, IL-6 and IL-23 and drives Tr1 differentiation. IFN-γ suppresses Th17 inducing osteoprotegerin (OPG) and drives IL-27 production, thereby promoting Tr1 differentiation. Furthermore, PD-1/PDL-1 signaling and bacterial peptides along with vasoactive intestinal peptide (VIP) drive IL-10 production which also induces Tr1 differentiation. Moreover, ICOS/ICOSL signalling as well as TGF-β production by DCs has also been implicated in driving Tr1 differentiation.

Figure 2

DCs drive differentiation of foxp3⁺ inducible regulatory T cells. (iTregs). DCs secrete TGF-β, which induces foxp3 in naive T cells, driving differentiation of naive T cells into iTregs. Activation of AhR and TLR9 drives induction of IDO, which catalyzes tryptophan metabolism. Tryptophan metabolites promote iTreg generation through induction of TGF-β production and suppression of Th17 inducing cytokine, IL-6. Furthermore, uptake of apoptotic DCs by viable DCs along with exposure to haptens, glucocorticoids and UV radiation also induces TGF-β production, which drives iTreg differentiation. Other signals such as RANK/RANKL signalling by vitamin D treated keratinocytes and treatment of DCs with vasoactive intestinal peptide (VIP), hepatocyte growth factor (HGF) and prostaglandin-D2 (PGD2) also promote iTreg differentiation. Moreover, retinoic acid promotes iTreg differentiation by suppressing cytokines which are inhibitory to iTreg differentiation and targeting of antigen to DEC205 drives iTreg differentiation through a TGF-β dependent mechanism.