Background/Purpose: Human plasmacytoid dendritic cells (pDCs) play a vital role in modulating immune responses. pDCs can produce massive amounts of type I IFNs in response to nucleic acids via toll-like receptors (TLRs) and they are known to possess weak antigen-presenting properties inducing CD4⁺ T cell activation. Previous data showed a cross-regulation between TNF-α and IFN-α but the effect of TNF-α on pDCs remains unclear. The aim of this study was to investigate how TNF-α regulates the immune function of human pDCs.

Methods: Freshly isolated peripheral blood mononuclear cells were treated with TNF-α, TLR7 and TLR9 synthetic agonists. pDCs were immunophenotyped using flow cytometry. RNA from sorted pDCs was extracted and sequenced using Smart-seq2 for sensitive full-length transcriptome profiling. For pDC/T cell co-culture, fresh or TNF-α-treated pDCs were cultured with naïve CD4⁺ T cells for 5 days. The production of cytokines was measured by intracellular staining and ELISA.

Results: Upon stimulation with TLR7 and TLR9 agonists, there were three main pDC populations: non-producers, TNF-α-producers, TNF-α/IFN-α-producers. Exogenous TNF-α significantly reduced the production of both IFN-α and TNF-α in TLR9-stimulated pDCs but only IFN-α in TLR7-stimulated pDCs. Neutralization of autologous TNF-α with anti-TNF antibody partially sustained IFN-α secretion by TLR9-stimulated pDCs after 24 hours. Exogenous TNF-α significantly promoted pDC maturation by upregulation of costimulatory molecules and chemokine receptors such as CD80, CD86, HLA-DR, and CCR7. RNA-sequencing data analysis suggested that TNF-α inhibits IFN-α production by interfering with the IRF7 and NFκB pathways but promotes antigen processing and presentation pathways as well as T cell activation and differentiation. Indeed, the in vitro co-culture showed that TNF-α-treated pDCs induced higher CD4⁺ T cell proliferation and favoured Th1/Th17 polarization.

Conclusion: Although pDCs possess weak antigen-presenting properties, TNF-α can enhance pDC maturation by switching their main role as IFN-α-producing cells to a more conventional DC phenotype. The functional status of pDCs might be strongly influenced by overall inflammatory environment and TNF-α might regulate IFN-α-mediated aspects of a range of autoimmune and inflammatory diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tnf-%ce%b1-regulates-plasmacytoid-dendritic-cells-by-suppressing-ifn-%ce%b1-production-and-enhancing-th1-and-th17-cell-differentiation/