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 a potential to prime naïve CD4⁺ T cells to differentiate into IL-10-producing T regulatory cells through inducible costimulatory ligand (ICOS-L), which has been implicated in the induction of T regulatory cell-mediated peripheral tolerance. Although PDCs in response to TLR-stimuli show a functional property not only to upregulate ICOS-L but also to produce a large amount of type I IFNs and proinflammatory cytokines TNF and IL-6, the role of these cytokines in T cell priming has remained elusive. Therefore, we here investigate functional involvement of PDC-derived cytokines in the generation of IL-10-producing T regulatory cells through ICOS-L. We cultured naïve and memory CD4⁺ T cells with anti-CD3 mAbs in the presence or absence of ICOS-L-transfected L cells for 5 to 7 days. Addition of IFN-α to the T cell culture enhanced the ICOS-L-mediated generation of IL-10-producing T cells from both naïve and memory CD4⁺ T cells. However, IL-10 production in T cells was not significantly increased by IFN-α single stimulation. Thus, type I IFNs act as a supplementary factor for the IL-10 production during T cell polarization. We also found that PDC-derived TNF-α contributed to the induction of ICOS-L expression on PDCs in an autocrine manner. In addition, PDC-derived IL-6 induced ICOSL-mediated IL-10-producing T cell generation under Th2 condition. However, ICOS-L, type I IFNs, and IL-6 under Th2 condition did not induce FOX-P3 expression on T cells. Our results suggest that PDC-derived cytokines, TNF, IL-6, and Type I IFNs play a complementary role for the generation of IL-10-producing T cells through ICOSL, which may contributes to peripheral tolerance for controlling an excessive immune response.