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

ABSTRACT: 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-? and IFN-?, but many questions remain about the effect of TNF-? in regulating human pDCs. In this study, we showed that TNF-? significantly inhibited the secretion of IFN-? and TNF-? of TLR-stimulated pDCs. Instead, exogenous TNF-? 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-? inhibited IFN-? and TNF-? production by downregulating IRF7 and NF-?B pathways, while it promoted Ag processing and presentation pathways as well as T cell activation and differentiation. Indeed, TNF-?-treated pDCs induced in vitro higher CD4⁺ T cell proliferation and activation, enhancing the production of Th1 and Th17 cytokines. In conclusion, TNF-? favors pDC maturation by switching their main role as IFN-?-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-? might regulate IFN-?-mediated aspects of a range of autoimmune and inflammatory diseases.

SUBMITTER: Psarras A

PROVIDER: S-EPMC7851743 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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

Psarras Antonios A Antanaviciute Agne A Alase Adewonuola A Carr Ian I Wittmann Miriam M Emery Paul P Tsokos George C GC Vital Edward M EM

Journal of immunology (Baltimore, Md. : 1950) 20210113 4

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<sup>+</sup> T cell activation. Previous studies showed a cross-regulation between TNF-α and IFN-α, but many questions remain about the effect of TNF-α in regulating human pDCs. In this study, we showed that TNF-α significantly inhibited the se ...[more]

PMID: 33441439

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Project description:Recent studies have reported that the crosslinking of regulatory receptors (RRs), such as blood dendritic cell antigen 2 (BDCA-2) (CD303) or ILT7 (CD85g), of plasmacytoid dendritic cells (pDCs) efficiently suppresses the production of type I interferons (IFN-I, ?/?/?) and other cytokines in response to toll-like receptor 7 and 9 (TLR7/9) ligands. The exact mechanism of how this B cell receptor (BCR)-like signaling blocks TLR7/9-mediated IFN-I production is unknown. Here, we stimulated BCR-like signaling by ligation of RRs with BDCA-2 and ILT7 mAbs, hepatitis C virus particles, or BST2 expressing cells. We compared BCR-like signaling in proliferating pDC cell line GEN2.2 and in primary pDCs from healthy donors, and addressed the question of whether pharmacological targeting of BCR-like signaling can antagonize RR-induced pDC inhibition. To this end, we tested the TLR9-mediated production of IFN-I and proinflammatory cytokines in pDCs exposed to a panel of inhibitors of signaling molecules involved in BCR-like, MAPK, NF-?B, and calcium signaling pathways. We found that MEK1/2 inhibitors, PD0325901 and U0126 potentiated TLR9-mediated production of IFN-I in GEN2.2 cells. More importantly, MEK1/2 inhibitors significantly increased the TLR9-mediated IFN-I production blocked in both GEN2.2 cells and primary pDCs upon stimulation of BCR-like or phorbol 12-myristate 13-acetate-induced protein kinase C (PKC) signaling. Triggering of BCR-like and PKC signaling in pDCs resulted in an upregulation of the expression and phoshorylation of c-FOS, a downstream gene product of the MEK1/2-ERK pathway. We found that the total level of c-FOS was higher in proliferating GEN2.2 cells than in the resting primary pDCs. The PD0325901-facilitated restoration of the TLR9-mediated IFN-I production correlated with the abrogation of MEK1/2-ERK-c-FOS signaling. These results indicate that the MEK1/2-ERK pathway inhibits TLR9-mediated type I IFN production in pDCs and that pharmacological targeting of MEK1/2-ERK signaling could be a strategy to overcome immunotolerance of pDCs and re-establish their immunogenic activity.

Dataset Information

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

Publications

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

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