Plasmacytoid dendritic cells have a cytokine-producing capacity to enhance ICOS ligand-mediated IL-10 production during T-cell priming.

Plasmacytoid dendritic cells (pDCs) have the potential to prime CD4(+) T-cells to differentiate into IL-10-producing T regulatory cells through preferential expression of inducible co-stimulatory ligand (ICOS-L). Although pDCs produce cytokines such as type-I IFNs, TNF-α, or IL-6 accompanying up-regulation of ICOS-L expression during activation in response to toll-like receptor (TLR)-ligands or IL-3, the roles of the pDC-derived cytokines in T-cell priming remain largely elusive. Therefore, we investigated the functional involvement of these cytokines in generating IL-10-producing T regulatory cells. We found that either IFN-α or IL-6 enhanced the pDC- or ICOS-L-driven generation of IL-10-producing T-cells from naive CD4(+) T-cells and their regulatory functions. However, IFN-α stimulation in the absence of ICOS-L showed only a marginal tendency to increase the T-cell production of IL-10 and thus pDC-derived type-I IFNs in response to CpG could function together with ICOS-L. In addition, IL-6 functioned to generate IL-10-producing T-cells only on T-cell priming by pDCs activated by IL-3 or under IL-4-mediated T(h)2 conditions. Thus, type-I IFNs and IL-6 act as supplementary factors for the ICOS-L-dependent IL-10-producing T-cell differentiation in pDCs activated along the TLR-dependent and IL-3-dependent pathways, respectively. We also showed that pDC-derived TNF-α induced ICOS-L expression on pDCs in an autocrine manner and that IL-6 promoted ICOS expression on T-cells, contributing to the ICOS/ICOS-L-mediated T-cell response. Our results suggest that the ICOS-L-mediated tolerogenic pDC function in adaptive immunity is backed up by the elaborate cytokine-producing ability of pDCs.