TGF-β Suppresses β-Catenin-Dependent Tolerogenic Activation Program in Dendritic Cells

Lugt, Bryan Vander; Beck, Zachary T.; Fuhlbrigge, Robert C.; Hacohen, Nir; Campbell, James J.; Boes, Marianne

doi:10.1371/journal.pone.0020099

Cited by 22 publications

(39 citation statements)

References 23 publications

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“…and M.B., unpublished data, 2012). 26,27 Incubation of pp65 or pp65-IC did not result in overt increase of the costimulatory markers CD40, CD80, or CD86, with only a minor increase in CD86 expression in pp65-IC treated MoDCs. Therefore, we concluded that increased cross-presentation of pp65-IC is not caused by increased costimulatory molecule expression.…”

Section: Potentiation Of Viral Antigen Cross-presentation By Fc␥r Tarmentioning

confidence: 85%

Fcγ receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells

Flinsenberg¹,

Compeer²,

Koning

et al. 2012

Blood

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The reactivation of human cytomegalovirus (HCMV) poses a serious health threat to immune compromised individuals. As a treatment strategy, dendritic cell (DC) vaccination trials are ongoing. Recent work suggests that BDCA-3 ؉ (CD141 ؉ ) subset DCs may be particularly effective in DC vaccination trials. BDCA-3 ؉ DCs had however been mostly characterized for their ability to cross-present antigen from necrotic cells. We here describe our study of human BDCA-3 ؉ DCs in elicitation of HCMV-specific CD8 ؉ T-cell clones.

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Section: Potentiation Of Viral Antigen Cross-presentation By Fc␥r Tarmentioning

confidence: 85%

Fcγ receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells

Flinsenberg¹,

Compeer²,

Koning

et al. 2012

Blood

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“…This phenotype is similar to LCs from tamoxifen-treated TGF-β and TGF-βRII mice. Indeed, TGF-β has been shown to inhibit the noncanonical β-catenin pathway (29). One relatively unique aspect of this system is that TGF-β acts in an autocrine/ paracrine manner.…”

Section: Discussionmentioning

confidence: 99%

Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Bobr

Igyártó

Haley

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

103

101

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Langerhans cells (LCs) are skin-resident dendritic cells (DC) located in the epidermis that migrate to skin-draining lymph nodes during the steady state and in response to inflammatory stimuli. TGF-β1 is a critical immune regulator that is highly expressed by LCs. The ability to test the functional importance of LC-derived TGF-β1 is complicated by the requirement of TGF-β1 for LC development and by the absence of LCs in mice with an LC-specific ablation of TGF-β1 or its receptor. To overcome these problems, we have engineered transgenic huLangerin-CreER T2 mice that allow for inducible LC-specific excision. Highly efficient and LC-specific expression was confirmed in mice bred onto a YFP Cre reporter strain. We next generated huLangerin-CreER T2 × TGF-βRII fl and huLangerin-CreER T2 × TGF-β1 fl mice. Excision of the TGFβRII or TGFβ1 genes induced mass migration of LCs to the regional lymph node. Expression of costimulatory markers and inflammatory cytokines was unaffected, consistent with homeostatic migration. In addition, levels of p-SMAD2/3 were decreased in LCs from wild-type mice before inflammation-induced migration. We conclude that TGF-β1 acts directly on LCs in an autocrine/paracrine manner to inhibit steady-state and inflammationinduced migration. This is a readily targetable pathway with potential therapeutic implications for skin disease.skin immunology | pSMAD2/3 | tolerance

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“…␤-catenin is thus a necessary component of the signaling pathway induced by mechanical signals, and such pathway can be blocked by TGF-␤. 75 Based on these observations, Jiang et al suggested that the disruption of E-cadherin-mediated DC interactions constitutes one of the sterile triggers capable of generating tolerogenic DCs under steady-state conditions. 36 In that model, immunogenic TLR-mediated signals prevail over the E-cadherin-␤-catenin-mediated tolerogenic signals.…”

Section: Regulation Of E-cadherin/␤-catenin Function Influences the Dmentioning

confidence: 99%

“…36 This ␤-catenin-mediated induction of tolerogenic DC is inhibited by TGF-␤. 75 (C) E-cadherin is a selective marker for IL-4/IL-13-exposed macrophages and is STAT6/DAP12/polyamine-dependently induced. 90 For personal use only.…”

Section: E-cadherin As Marker For Colitogenic Dcsmentioning

confidence: 99%

Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

Bossche

Malissen

Mantovani

et al. 2012

Blood

140

121

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E-cadherin is best characterized as adherens junction protein, which through homotypic interactions contributes to the maintenance of the epithelial barrier function. In epithelial cells, the cytoplasmic tail of E-cadherin forms a dynamic complex with catenins and regulates several intracellular signal transduction pathways, including Wnt/␤-catenin, PI3K/Akt, Rho GTPase, and NF-B signaling. Recent progress uncovered a novel and critical role for this adhesion molecule in mononuclear phagocyte functions. Ecadherin regulates the maturation and migration of Langerhans cells, and its ligation prevents the induction of a tolerogenic state in bone marrow-derived dendritic cells (DCs). In this respect, the functionality of ␤-catenin could be instrumental in determining the balance between immunogenicity and tolerogenicity of DCs in vitro and in vivo. Fusion of alternatively activated macrophages and osteoclasts is also Ecadherin-dependent. In addition, the Ecadherin ligands CD103 and KLRG1 are expressed on DC-, T-, and NK-cell subsets and contribute to their interaction with E-cadherin-expressing DCs and macrophages. Here we discuss the regulation, function, and implications of Ecadherin expression in these central orchestrators of the immune system. (Blood. 2012;119(7):1623-1633) IntroductionCadherins are transmembrane or membrane-associated glycoproteins that mediate Ca 2ϩ -dependent cell-cell adhesion and have mainly been described for their instrumental role during morphogenesis of a variety of organs. 1 The cadherin superfamily composes classic type I cadherins, closely related type II cadherins, desmosomal cadherins, protocadherins, and several cadherin-related molecules. Cadherin-1 (encoded by Cdh1), also known as CD324, uvomorulin, or E-cadherin, in which the "E" stands for "epithelial," is the founding member of the classic type I cadherin family, which also includes N-cadherin (neural, Cdh2), P-cadherin (placental, Cdh3), Cdh4), and VE-cadherin (vascular endothelial, Cdh5). For several decades, E-cadherin has been known as a major constituent of adherens junctions (AJs), mediating strong homotypic adhesion between neighboring epithelial cells, thereby safeguarding epithelial barrier integrity. 2 The lack of functional tight junction and desmosome formation in the absence of E-cadherin emphasizes its central role in the regulation of epithelial cell-cell contacts. 3 Cell-cell adhesion is mainly executed by the formation of E-cadherin trans-homodimers. Indeed, the E-cadherin molecule contains an ectodomain composed of 5 extracellular cadherin (EC1-5) repeats (550 aa in total), in which EC1 composes the HAV peptide sequence responsible for homophilic interactions, a transmembrane region, and a cytoplasmic tail (150 aa). 2 The latter can be further subdivided into a ␤-catenin binding domain and a membrane proximal cytoplasmic/conserved domain, whose core sequence motif DEEGGGEED is important for p120-catenin binding, resulting in the stabilization of the E-cadherin/catenin complex at the cell surface. 4 E-cadhe...

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TGF-β Suppresses β-Catenin-Dependent Tolerogenic Activation Program in Dendritic Cells

Cited by 22 publications

References 23 publications

Fcγ receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells

Fcγ receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells

Autocrine/paracrine TGF-β1 inhibits Langerhans cell migration

Regulation and function of the E-cadherin/catenin complex in cells of the monocyte-macrophage lineage and DCs

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