Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells

Rutz, Sascha; Mordmüller, Benjamin; Sakano, Seiji; Scheffold, Alexander

doi:10.1002/eji.200526294

Cited by 94 publications

(79 citation statements)

References 57 publications

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“…However, not all pathogenic infections result in a Th2 response in the absence of IL-12 (37). These latter studies, along with the recently described role of notch ligands (19,21,44,45), suggest that there may be both Th1 and Th2 instructive signals that regulate the decision process. The data from the present studies further indicate that although MyD88 Ϫ/Ϫ DCs had a deficient expression of important instructive signals, they were able to provide stimulatory signals that are required for initial T cell activation.…”

Section: Discussionmentioning

confidence: 95%

MyD88-Mediated Instructive Signals in Dendritic Cells Regulate Pulmonary Immune Responses during Respiratory Virus Infection

Rudd

Schaller

Smit

et al. 2007

The Journal of Immunology

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Respiratory syncytial virus (RSV) is the leading cause of respiratory disease in infants worldwide. The induction of innate immunity and the establishment of adaptive immune responses are influenced by the recognition of pathogen-associated molecular patterns by TLRs. One of the primary pathways for TLR activation is by MyD88 adapter protein signaling. The present studies indicate that MyD88 deficiency profoundly impacts the pulmonary environment in RSV-infected mice characterized by the accumulation of eosinophils and augmented mucus production. Although there was little difference in CD4 T cell accumulation, there was also a significant decrease in conventional dendritic cells recruitment to the lungs of MyD88−/− mice. The exacerbation of RSV pathophysiology in MyD88−/− mice was associated with an enhanced Th2 cytokine profile that contributed to an inappropriate immune response. Furthermore, bone marrow-derived dendritic cells (BMDC) isolated from MyD88−/− mice were incapable of producing two important Th1 instructive signals, IL-12 and delta-like4, upon RSV infection. Although MyD88−/− BMDCs infected with RSV did up-regulate costimulatory molecules, they did not up-regulate class II as efficiently and stimulated less IFN-γ from CD4+ T cells in vitro compared with wild-type BMDCs. Finally, adoptive transfer of C57BL/6 BMDCs into MyD88−/− mice reconstituted Th1 immune responses in vivo, whereas transfer of MyD88−/− BMDCs into wild-type mice skewed the RSV responses toward a Th2 phenotype. Taken together, our data indicate that MyD88-mediated pathways are essential for the least pathogenic responses to this viral pathogen through the regulation of important Th1-associated instructive signals.

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Section: Discussionmentioning

confidence: 95%

MyD88-Mediated Instructive Signals in Dendritic Cells Regulate Pulmonary Immune Responses during Respiratory Virus Infection

Rudd

Schaller

Smit

et al. 2007

The Journal of Immunology

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“…For example, lateral inhibition and prosensory functions of Notch signaling in the mouse inner ear are distinctly mediated by Jag1 and Dll1 respectively (Brooker et al, 2006). Also, during T lymphocyte development, the activation and proliferation of T helper cells is differentially regulated by Dll1, Dll4, and Jag1 (Rutz et al, 2005). The exclusivity of the expression patterns observed for these ligands could explain the differences in embryonic lethality and in phenotypes observed in the Jag1 and Dll4 null mice.…”

Section: Jagged1 and Delta-like4 Expression In Vascular Smooth Musclementioning

confidence: 99%

Notch expression patterns in the retina: An eye on receptor–ligand distribution during angiogenesis

Hofmann¹,

Iruela‐Arispe

2007

Gene Expression Patterns

100

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The critical contribution of the Notch signaling pathway to vascular morphogenesis has been underscored by loss-of-function studies in mouse and zebrafish. Nonetheless, a comprehensive understanding as to how this signaling system influences the formation of blood vessels at the cellular and molecular level is far from reached. Here, we provide a detailed analysis of the distribution of active Notch1 in relation to its DSL (Delta, Serrate, Lag2) ligands, Jagged1, Deltalike1, and Delta-like4, during progressive stages of vascular morphogenesis and maturation. Important differences in the cellular distribution of Notch ligands were found. Jagged1 (Jag1) was detected in "stalk cells" of the leading vasculature and at arterial branch points, a site where Deltalike4 (Dll4) was clearly absent. Dll4 was the only ligand expressed in "tip cells" at the end of the growing vascular sprouts. It was also present in stalk cells, capillaries, arterial endothelium, and in mural cells of mature arteries in a homogenous manner. Delta-like1 (Dll1) was observed in both arteries and veins of the developing network, but was also excluded from mature arterial branch points. These findings support alternative and distinct roles for Notch ligands during the angiogenic process.

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“…In a heart allograft mouse model, overexpression of Delta-1 on alloantigen-bearing cells could induce specific unresponsiveness to the same alloantigen (101). Furthermore, Notch ligands Delta-1 (102) and Jagged-1 (98,102,103) inhibited proliferation, and/or cytokine production, after stimulation of CD4 + T cells with different stimuli, which correlated with suppression of transcription factors NF-AT, AP-1 and NF-κB (102) and upregulation of GRAIL (gene related to anergy in lymphocytes) in CD4 + T cells (103). The inhibition of T cell proliferation was Notch signaling dependent because γ-secreatase significantly block this effect.…”

Section: Notch Signaling and Dendritic Cell Functionmentioning

confidence: 99%

“…Activation of Notch by Jagged-1 and Delta-1 inhibited T cell proliferation whereas Delta-4 enhanced T-cell activation and proliferation. (102). It is possible that the discrepancies could also be due to the existence of Notch-independent effects of some components of Notch signaling pathway such as Mastermind (106,107) and RBP-J (108).…”

Section: Notch Signaling and Dendritic Cell Functionmentioning

confidence: 99%

Notch signaling in differentiation and function of dendritic cells

Cheng

Gabrilovich

2007

Immunol Res

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Hematopoietic stem cells give rise to multiple lineages of cells. This process is governed by a tightly controlled signaling network regulated by cytokines and a direct cell-cell. Notch signaling represents one of the major pathways activated during direct interaction between hematopoietic progenitor cells and bone marrow stroma. A critical role of Notch signaling in differentiation of T and B lymphocytes has now been established. Until recently, the role of Notch signaling in the development of myeloid cells and particular dendritic cells remained unclear. In this review we discuss recent exciting findings that shed light on the critical role of Notch in differentiation and the function of dendritic cells and its impact on immune responses.

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Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells

Cited by 94 publications

References 57 publications

MyD88-Mediated Instructive Signals in Dendritic Cells Regulate Pulmonary Immune Responses during Respiratory Virus Infection

MyD88-Mediated Instructive Signals in Dendritic Cells Regulate Pulmonary Immune Responses during Respiratory Virus Infection

Notch expression patterns in the retina: An eye on receptor–ligand distribution during angiogenesis

Notch signaling in differentiation and function of dendritic cells

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