Human Plasmacytoid Dendritic Cells Support Th17 Cell Effector Function in Response to TLR7 Ligation

Yu, Chunfeng; Peng, Wenming; Oldenburg, Johannes; Hoch, J.; Bieber, Thomas; Limmer, Andreas; Hartmann, Gunther; Barchet, Winfried; Eis‐Hübinger, Anna Maria; Novak, Natalija

doi:10.4049/jimmunol.0901706

Cited by 98 publications

(94 citation statements)

References 53 publications

(58 reference statements)

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“…Whereas pDC have been largely implicated in tolerance induction through Treg generation, our data and others demonstrated their role in the development of pathogenic Th17 cells (13,14). Indeed, human pDC stimulated through TLR7 have been demonstrated to both promote Th17 cell commitment and amplify Th17 effector functions (14). This further supported the role of pDC such as a cellular source of TGF-b, like TGF-b-producing Tregs (32,34), to polarize Th17 cells.…”

Section: Discussionsupporting

confidence: 78%

“…pDC are influenced by microenvironment signals like other APC. Whereas pDC have been largely implicated in tolerance induction through Treg generation, our data and others demonstrated their role in the development of pathogenic Th17 cells (13,14). Indeed, human pDC stimulated through TLR7 have been demonstrated to both promote Th17 cell commitment and amplify Th17 effector functions (14).…”

Section: Discussionmentioning

confidence: 57%

“…Moreover, data supported a role of pDC in tolerance induction through several mechanisms including IDO activity, IL-10 secretion, or regulatory T cell (Treg) induction (10)(11)(12). In contrast, data are emerging implicating mouse and human pDC in IL-17-secreting T cell (Th17) differentiation (13,14). Recently, Th17 cells have been described as the major pathological T cells in several inflammatory diseases such as in experimental autoimmune encephalomyelitis or arthritis (15).…”

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confidence: 99%

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TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

Bonnefoy

Couturier

Clauzon

et al. 2011

The Journal of Immunology

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TGF-β is required for both Foxp3+ regulatory T cell (Treg) and Th17 commitment. Plasmacytoid DCs (pDC) have been shown to participate to both Treg and Th17 commitment as well. However, few studies have evaluated the direct effect of TGF-β on pDC, and to our knowledge, no study has assessed the capacity of TGF-β–exposed pDC to polarize naive CD4+ T cells. In this paper, we show that TGF-β–treated pDC favor Th17 but not Treg commitment. This process involves a TGF-β/Smad signal, because TGF-β treatment induced Smad2 phosphorylation in pDC and blockade of TGF-β signaling with the SD208 TGF-βRI kinase inhibitor abrogated Th17 commitment induced by TGF-β–treated pDC. Moreover, TGF-β mRNA synthesis and active TGF-β release were induced in TGF-β–treated pDC and anti–TGF-β Ab blocked Th17 commitment. Unexpectedly, TGF-β treatment also induced increased IL-6 production by pDC, which serves as the other arm for Th17 commitment driven by TGF-β–exposed pDC, because elimination of IL-6–mediated signal with either IL-6– or IL-6Rα–specific Abs prevented Th17 commitment. The in vivo pathogenic role of TGF-β–treated pDC was further confirmed in the Th17-dependent collagen-induced arthritis model in which TGF-β–treated pDC injection significantly increased arthritis severity and pathogenic Th17 cell accumulation in the draining lymph nodes. Thus, our data reveal a previously unrecognized effect of TGF-β–rich environment on pDC ability to trigger Th17 commitment. Such findings have implications in the pathogenesis of autoimmune diseases or immune responses against mucosal extracellular pathogens.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 57%

mentioning

confidence: 99%

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TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

Bonnefoy

Couturier

Clauzon

et al. 2011

The Journal of Immunology

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“…PDCs-derived CXCL10 was also shown to be responsible for recruiting CXCR3 + T cells to cutaneous LE lesions [51], and the cerebrospinal fluid of patients with neuropsychiatric lupus [87]. In this context, PDCs have also been implicated in autoimmune diseases by promoting Th17 immune responses through the production of IL1b and IL23p19 [88,89]. Moreover, by secreting CCL4, PDCs might be involved in regulatory T cell recruitment to the tumor site, representing an additional mechanism for controlling immune function [90].…”

Section: Reviewmentioning

confidence: 99%

Trafficking properties of plasmacytoid dendritic cells in health and disease

Sozzani

Vermi

Prete

et al. 2010

Trends in Immunology

139

151

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“…DCs are considered a cellular source of IL-6 and IL-23. TLR ligation on a human DC induces high expression of IL-23p19 and IL-6, which is positively correlated with the elevated IL-17A levels among cocultured T cells [17,18] .…”

Section: Introductionmentioning

confidence: 94%

Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZB×NZW F1 mice via interference with TLR-mediated APC response

Lin

et al. 2013

Acta Pharmacol Sin

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Aim: To examine the therapeutic effects and underlying mechanisms of DZ2002, a reversible S-adenosyl-L-homocysteine hydrolase (SAHH) inhibitor, on lupus-prone female NZB×NZW F1 (NZB/W F1) mice. Methods: Female NZB/W F1 mice were treated orally with DZ2002 (0.5 mg·kg -1 ·d -1 ) for 11 weeks, and the proteinuria level and body weight were monitored. After the mice ware euthanized, serum biochemical parameters and renal damage were determined. Splenocytes of NZB/W F1 mice were isolated for ex vivo study. Toll-like receptor (TLR)-stimulated human peripheral blood mononuclear cells (PBMCs) or murine bone marrow-derived dendritic cells (BMDCs) were used for in vitro study. Results: Treatment of the mice with DZ2002 significantly attenuated the progression of glomerulonephritis and improved the overall health. The improvement was accompanied by decreased levels of nephritogenic anti-dsDNA IgG2a and IgG3 antibodies, serum IL-17, IL-23p19 and TGF-β. In ex vivo studies, treatment of the mice with DZ2002 suppressed the development of pathogenic Th17 cells, significantly decreased IL-17, TGF-β, IL-6, and IL-23p19 production and impeded activation of the STAT3 protein and JNK/NF-κB signaling in splenocytes. DZ2002 (500 μmol/L) significantly suppressed TLR agonists-stimulated up-regulation in IL-6, IL-12p40, TNF-α, and IgG and IgM secretion as well as in HLA-DR and CD40 expression of dendritic cells among human PBMCs in vitro. DZ2002 (100 μmol/L) also significantly suppressed TLR agonists-stimulated up-regulation in IL-6 and IL-23p19 production in murine BMDCs, and prevented Th17 differentiation and suppressed IL-17 secretion by the T cells in a BMDC-T cell co-culture system. Conclusion: DZ2002 effectively ameliorates lupus syndrome in NZB/W F1 mice by regulating TLR signaling-mediated antigen presenting cell (APC) responses.

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Human Plasmacytoid Dendritic Cells Support Th17 Cell Effector Function in Response to TLR7 Ligation

Cited by 98 publications

References 53 publications

TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

TGF-β–Exposed Plasmacytoid Dendritic Cells Participate in Th17 Commitment

Trafficking properties of plasmacytoid dendritic cells in health and disease

Therapeutic effects of DZ2002, a reversible SAHH inhibitor, on lupus-prone NZB×NZW F1 mice via interference with TLR-mediated APC response

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