4.6 Article

Ligation of Notch Receptors in Human Conventional and Plasmacytoid Dendritic Cells Differentially Regulates Cytokine and Chemokine Secretion and Modulates Th Cell Polarization

Journal

JOURNAL OF IMMUNOLOGY
Volume 186, Issue 12, Pages 7006-7015

Publisher

AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1100203

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Funding

  1. Fondo de Investigaciones Sanitarias of the Spanish National Institutes of Health [FIS 06/0453]
  2. Instituto de Salud Carlos III of the Spanish National Institutes of Health [FI07/00054]
  3. Spanish Ministry of Science and Innovation and Blood and Tissue Bank [PTQ-09-02-017050]
  4. Agencia de Gestio d'Ajuts Universitaris i de Recerea of the Catalan Government [2010FI_B1 00023]
  5. Instituto de Salud Carlos III and Direccio d'Estrategia i Coordinacio [CES 07/015]
  6. Health Department of the Catalan Government

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Notch signaling is involved in multiple cellular processes. Recent data also support the prominent role of Notch signaling in the regulation of the immune response. In this study, we analyzed the expression and function of Notch receptors and ligands on both human blood conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs). The expression and modulation upon TLR activation of Notch molecules partially differed between cDCs and pDCs, but functional involvement of the Notch pathway in both cell types was clearly revealed by specific inhibition using DAPT. Beyond the induction of Notch target genes and modulation of maturation markers, Notch pathway was also involved in a differential secretion of some specific cytokines/chemokines by DC subsets. Whereas Notch ligation induced IL-10 and CCL19 secretion in cDCs, Notch inhibition resulted in a diminished production of these proteins. With regard to pDCs, Notch activation induced TNF-alpha whereas Notch inhibition significantly abrogated the secretion of CCL19, CXCL9, CXCL10, and TNF-alpha. Additionally, Notch modulation of DC subsets differentially affected Th polarization of allostimulated T cells. Our results suggest that the Notch pathway may function as an additional mechanism controlling human DC responses, with differential activity on cDCs and pDCs. This control mechanism may ultimately contribute to define the local milieu promoted by these cells under the particular conditions of the immune response. The Journal of Immunology, 2011, 186: 7006-7015.

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