The Notch Ligand Jagged-1 Is Able to Induce Maturation of Monocyte-Derived Human Dendritic Cells

Weijzen, Sanne; Velders, Markwin P.; Elmishad, Amira G.; Bacon, Patricia; Panella, Jeffrey; Nickoloff, Brian J.; Miele, Lucio; Kast, W. Martin

doi:10.4049/jimmunol.169.8.4273

Cited by 91 publications

(90 citation statements)

References 62 publications

(49 reference statements)

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“…Maturation of Human DCs-The maturation of DCs often involves the spectrum of cellular signaling events, including TLR2-dependent activation of NOTCH signaling, which is suggested to play an important role in critical cell fate decisions during DC maturation and subsequent priming of effector T cell responses (37,38). In this regard, we and others have previously shown that TLR2 stimulation leads to up-regulation of NOTCH1 and activation of the NOTCH1 signaling pathway by inducing the formation of a cleavage product of NOTCH1 (NICD) as well as robust activation of Jagged1 expression, a NOTCH1 receptor ligand (39 -44).…”

Section: Notch1-pi3k Signaling Dynamics Integrated Into Signaling Cohmentioning

confidence: 99%

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Ghorpade

Kaveri

Bayry

et al. 2011

Journal of Biological Chemistry

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Dendritic cells (DCs) as sentinels of the immune system are important for eliciting both primary and secondary immune responses to a plethora of microbial pathogens. Cooperative stimulation of a complex set of pattern-recognition receptors, including TLR2 and nucleotide-binding oligomerization domain (NOD)-like receptors on DCs, acts as a rate-limiting factor in determining the initiation and mounting of the robust immune response. It underscores the need for "decoding" these multiple receptor interactions. In this study, we demonstrate that TLR2 and NOD receptors cooperatively regulate functional maturation of human DCs. Intriguingly, synergistic stimulation of TLR2 and NOD receptors renders enhanced refractoriness to TGF-␤-or CTLA-4-mediated impairment of human DC maturation. Signaling perturbation data suggest that NOTCH1-PI3K signaling dynamics assume critical importance in TLR2-and NOD receptor-mediated surmounting of CTLA-4-and TGF-␤-suppressed maturation of human DCs. Interestingly, the NOTCH1-PI3K signaling axis holds the capacity to regulate DC functions by virtue of PKC␦-MAPK-dependent activation of NF-B. This study provides mechanistic and functional insights into TLR2-and NOD receptor-mediated regulation of DC functions and unravels NOTCH1-PI3K as a signaling cohort for TLR2 and NOD receptors. These findings serve in building a conceptual foundation for the design of improved strategies for adjuvants and immunotherapies against infectious diseases.

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Section: Notch1-pi3k Signaling Dynamics Integrated Into Signaling Cohmentioning

confidence: 99%

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Ghorpade

Kaveri

Bayry

et al. 2011

Journal of Biological Chemistry

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“…Here, we found that HES, the main transcription factor donwstream of Notch, induced a strong transactivation of TGF-ßRII by binding the TGF-βRII promoter through its DNA-binding activity. Taken together, this set of findings is consistent with the conclusion that Notch signaling plays an important role in facilitating TGF-β signaling in effector function and, in turn, TGF-β signaling amplifies these effects by upregulating HES.There is clear evidence that stimulation of APCs (dendritic cells, DCs) via Jagged enhances APC function from the point of view of maturation markers, cytokine production, and differentiation effects on T cells [17]. This raises the question of whether DCs are exposed to Notch ligands in the microenvironments where they reside.…”

supporting

confidence: 86%

Notch activation on effector T cells increases their sensitivity to Treg cell‐mediated suppression through upregulation of TGF‐βRII expression

et al. 2012

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Notch proteins play an important role in embryonic development and cell-fate decisions. Notch influences also the activation and differentiation of peripheral T cells. Here, we investigated whether Notch signaling modulates the response of effector T cells to regulatory T (Treg) cells. Pre-exposure of CD4 + CD25 − effector T cells to the Notch ligandsDelta-4 and Jagged-1, but not Delta-1, increases significantly effector T-cell sensitivity to Treg cell-mediated suppression through upregulation of TGF-βRII expression and increased levels of the phosphorylated form of the Smad 3 protein. This effect is relieved by anti-TGF-β Abs. We demonstrate that HES (hairy and enhancer of split), the main transcription factor downstream of Notch, induces strong transactivation of TGF-ßRII by binding the TGF-βRII promoter through its DNA-binding domain. Thus, the crosstalk between Notch and the TGF-β pathway leads to potentiation of the suppressive effect of Treg cells. Keywords:Immune regulation r Notch signaling r Regulatory T cells r TGF-βRII IntroductionThe Notch signaling system is conserved from Drosophila to humans and regulates cell differentiation, proliferation, and survival. Notch pathways play an important role in embryonic development, T-cell development and function, and in disease processes, including carcinogenesis and autoimmunity. In mammals there are four Notch receptors (1-4) and five Notch ligands (Jagged-1, Jagged-2, Delta-like 1 (DL-1), [1].Notch proteins exert their pleiotropic effects through the regulation of expression of various downstream genes, many of which require the interaction of Notch proteins with the DNA binding transcription factor CSL (also known as CBF1, Su(H), Correspondence: Prof. Yves Levy e-mail: yves.levy@hmn.aphp.fr and LAG-1) in order to form a short-lived nuclear transcription complex [2]. After engagement with its ligands, successive proteolytic events cause clipping of the Notch protein. The first is mediated by ADAM proteases and the second by the γ-secretase complex, in which presenilins (PS1 and PS2) constitute the active center of the enzyme complex. These proteolytic events ultimately release the intracellular domain of Notch (NICD). The formation of a complex of activated intracellular Notch protein and CSL converts CSL from a transcriptional repressor to a transcriptional transactivator. The genes encoding the HES (hairy and enhancer of split) family of basic helix-loop-helix proteins are Notch targets that are known to be essential for T-cell development and signaling. * These authors have contributed equally to this work.www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1796-1803 Immunomodulation 1797In addition to influencing , Notch signaling has also been involved in the differentiation and expansion of regulatory T (Treg) cells [4]. Several reports have shown that the presence of Notch ligands, mostly of the Jagged family, can enhance Treg-cell differentiation and function in vitro [5]. For example, exposure of Treg cells to Jagged-2 expressed by hematopoietic progen...

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“…In addition, it has been shown that Notch signaling may selectively influence T cell differentiation depending, in some studies, on the type of Notch ligand inducing Notch activation (24 -27); this type of Notch signaling function could be considered positive or at least neutral because T cell differentiation occurs within a positive proliferative milieu. Finally, with respect to the effect of Notch signaling on APCs, there is clear evidence that stimulation of APCs (DCs) via Jagged1 enhances APC function from the point of view of maturation markers, cytokine production, and differentiating effects on T cells (43). Overall, therefore, whether one considers the T cell or the APC the main target of Treg suppression, there is no consistent evidence that Notch signaling has the required negative effects that one would expect of a mediator of suppression.…”

Section: Discussionmentioning

confidence: 99%

Notch1 Signaling and Regulatory T Cell Function

Asano

Watanabe

Kitani

et al. 2008

The Journal of Immunology

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Previous studies have shown that the Notch1 and TGF-β signaling pathways are mutually re-enforcing. Given recent evidence that regulatory T cell (Treg) effector function is mediated by TGF-β signaling, we investigated whether Notch1 signaling also participated in Treg effector function. Initial studies showed that Notch1 ligands, particularly Jagged1, are present on Tregs and that, indeed, blockade of Notch1 signaling with an anti-Jagged1 or a blocking anti-Notch1 Ab inhibits Treg suppressor function in vitro. We then showed that a signaling component generated by Notch1 activation (Notch1 intracellular domain) of dendritic cells physically interacts with a signaling component generated by TGF-β signaling (pSmad3). Furthermore, this interaction has functional downstream effects because over-expression of Notch1 intracellular domain facilitates pSmad3 translocation to the nucleus and enhances pSmad3 transcriptional activity of a Smad-sensitive promoter linked to a luciferase reporter. Finally, we showed that blockade of TGF-β signaling and Notch signaling did not have additive inhibitory effects on Treg suppressor function. These results are consistent with the conclusion that Notch1 signaling facilitates TGF-β-mediated effector function of Tregs.

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The Notch Ligand Jagged-1 Is Able to Induce Maturation of Monocyte-Derived Human Dendritic Cells

Cited by 91 publications

References 62 publications

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Cooperative Regulation of NOTCH1 Protein-Phosphatidylinositol 3-Kinase (PI3K) Signaling by NOD1, NOD2, and TLR2 Receptors Renders Enhanced Refractoriness to Transforming Growth Factor-β (TGF-β)- or Cytotoxic T-lymphocyte Antigen 4 (CTLA-4)-mediated Impairment of Human Dendritic Cell Maturation

Notch activation on effector T cells increases their sensitivity to Treg cell‐mediated suppression through upregulation of TGF‐βRII expression

Notch1 Signaling and Regulatory T Cell Function

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