The mucosal factors retinoic acid and TGF-β1 induce phenotypically and functionally distinct dendritic cell types.

Non-inflammatory dendritic cell (DC) subsets play an essential role in preventing massive inflammation in mucosal tissues. We investigated whether mucosa-related factors, namely retinoic acid (RA) and transforming growth factor-β (TGF-β1), can induce such DC types. DCs were differentiated from monocytes in the absence or presence TGF-β1 and RA. The phenotype as well as responsiveness to bacterial ligands was studied in detail. Compared to monocyte-derived DCs (moDCs), the expression of co-stimulatory molecule CD86 and DC maturation marker CD83 were strongly reduced by RA and TGF-β1. In addition, both RA- and TGF-β1-induced DCs showed strongly decreased responsiveness to stimulation with the bacterial ligands lipopolysaccharide and peptidoglycan, and produced significantly lower levels of the pro-inflammatory cytokines IL-12 and TNF-α compared to moDCs, whilst IL-10 production was not significantly reduced. DCs differentiated under the influence of RA uniquely expressed markers related to intestinal homing (CD103 and integrin β7). In addition, CCR7, which mediates homing to lymph nodes, was expressed by DCs differentiated in the presence of RA, and also to a lesser extent by the other DC types. Furthermore, whereas moDCs and TGF-β1-derived moDCs expressed high levels of CD32, RA-derived DCs lacked CD32 expression but expressed high levels of CD64, suggesting that RA-DCs may primarily respond to soluble proteins and moDCs, and TGF-β DCs to immune complexes. The data presented here support the hypothesis that the mucosal factors TGF-β1 and RA, which can also be provided through dietary intake of dairy products, result in functionally and phenotypically distinct DC types with non-inflammatory properties.