TNF-alpha Regulates Human Plasmacytoid Dendritic Cells by Suppressing IFN-alpha Production and Enhancing T Cell Activation

Human plasmacytoid dendritic cells (pDCs) play a vital role in modulating immune responses. They can produce massive amounts of type I IFNs in response to nucleic acids via TLRs, but they are also known to possess weak Ag-presenting properties inducing CD4(+) T cell activation. Previous studies showed a cross-regulation between TNF-alpha and IFN-alpha, but many questions remain about the effect of TNF-alpha in regulating human pDCs. In this study, we showed that TNF-alpha significantly inhibited the secretion of IFN-alpha and TNF-alpha of TLR-stimulated pDCs. Instead, exogenous TNF-alpha promoted pDC maturation by upregulating costimulatory molecules and chemokine receptors such as CD80, CD86, HLA-DR, and CCR7. Additionally, RNA sequencing analysis showed that TNF-alpha inhibited IFN-alpha and TNF-alpha production by downregulating IRF7 and NF-kappaB pathways, while it promoted Ag processing and presentation pathways as well as T cell activation and differentiation. Indeed, TNF-alpha-treated pDCs induced in vitro higher CD4(+) T cell proliferation and activation, enhancing the production of Th1 and Th17 cytokines. In conclusion, TNF-alpha favors pDC maturation by switching their main role as IFN-alpha-producing cells to a more conventional dendritic cell phenotype. The functional status of pDCs might therefore be strongly influenced by their overall inflammatory environment, and TNF-alpha might regulate IFN-alpha-mediated aspects of a range of autoimmune and inflammatory diseases.