title: Plasmacytoid dendritic cells have a cytokine-producing capacity to enhance ICOS ligand-mediated IL-10 production during T-cell priming.
abstract: 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.
authors.affiliation: First Department of Internal Medicine, Kansai Medical University, 10-15, Fumizono-Cho,  Moriguchi-City, Osaka, 570-8506, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ogata
authors.forename: Tomoki
authors.initials: T
authors.lastname: Ito
authors.forename: Keiko
authors.initials: K
authors.lastname: Shimamoto
authors.forename: Takahisa
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Naoko
authors.initials: N
authors.lastname: Satsutani
authors.forename: Rie
authors.initials: R
authors.lastname: Miyamoto
authors.forename: Shosaku
authors.initials: S
authors.lastname: Nomura
mesh_terms: D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000235:genetics / Q000378:metabolism*; D007375:Interleukin-1 / Q000276:immunology; D008213:Lymphocyte Activation; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058408:Th1-Th2 Balance; D015854:Up-Regulation
chemical_list: C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D007375:Interleukin-1