Analysis of Notch-driven Regulation of Dendritic Cell Function PDF Download

Author: Alborz Borjian
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Languages : en
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Book Description
"An effective immune response against pathogens or cancer requires proper guidance of the immune system. Being the first responders in innate immunity, Dendritic Cells (DCs) provide essential and differentiation cues to T cells, guiding them down specific effector lineages. Cell-cell communication through Notch signaling is initiated by trans-binding of receptor and ligand on neighboring cells to guide various cell fate decisions. However, recently it has been shown that cis-interaction of Notch receptor and Delta ligand in mammalian cells can result in inhibition of Notch signaling. DCs are known to express both Notch ligands and receptors. We have previously shown that DCs differentially express Notch ligands in response to stimuli associated with specific TH lineages. These findings suggest that relative abundance of Notch ligands to receptors may lead the cell to adopt a phenotype associated with signaling through either Notch ligand or receptor. Thereby, we hypothesize that the Notch signaling directly regulates DC function and therefore indirectly modulates T-cell polarization. To observe Notch signaling associated with different states of DC activation, we measured expression of components of Notch signal transduction in response to the Toll-like receptor (TLR) ligand lipopolysaccharide (LPS) and Leishmania parasites. Activation of DCs with TH1-directing LPS maintains the low Notch1 levels, but increases Notch2 expression. DCs infected with Leishmania remain immature, even if exposed to LPS subsequently, show higher Notch1 levels. Analysis of Notch1-deficient DCs, illustrated that Notch1 expression negatively regulates DC activation. Similarly, DCs stimulated with TH1-inducing agents maintain low Notch1 levels but have increased Delta4 expression. On the other hand, Notch2 expression positively regulates DC activation. Induced Notch2 expression leads to increased expression of co-stimulatory molecule CD86 and proinflammatory cytokine Interleukin 12 (IL-12). The increased Notch2 expression in DCs stimulated with LPS is, however, accompanied by a reduction in Jagged2 expression. Accordingly, Jagged2 is shown to negatively regulate IL-12 secretion. Such pattern of expression among Notch ligands and receptors (i.e. mutually exclusive expression of Notch1/Delta4 or Notch2/Jagged2) supports the evidence for cis-inhibition, a mechanism by which Notch receptors and ligands expressed on the same cell reciprocally inhibit one another. Such cis-interaction results in removal of the receptors and ligands from the cell surface and their subsequent proteolysis. All in all, our results propose that relative levels of Notch receptor and ligands can directly alter DC phenotype." --