TLR-activated conventional DCs promote γ-secretase-mediated conditioning of plasmacytoid DCs

Begoña Pérez-Cabezas, Mar Naranjo-Gómez, Marta Ruiz-Riol, Patricia Bastos-Amador, Marco A. Fernández, Francesc Carmona, Fatima Nuñez, Ricardo Pujol-Borrell, Francesc E. Borràs

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

Abstract

Cooperative events between DC subsets involve cell contact and soluble factors. Upon viral challenge, murine pDCs induce cDC cooperation through CD40-CD40L interactions and IL-15 secretion, whereas in humans, the same effect is mediated by IFN-α. Conversely, during bacterial infections, pDC maturation may be induced by activated cDCs, although no mechanisms had been described so far. Here, we investigate how human pDCs are "conditioned" by cDCs. Blood-borne DC subsets (cDCs and pDCs) were sorted from healthy donors. IL-3-maintained pDCs were cocul-tured with LPS-activated, poly (I:C)-activated, or control cDCs [cDCLPS, cDCP(I:C), cDCCTRL]. Coculture experiments showed that cDCLPS-conditioned pDCs up-regulated maturation markers, such as CD25 and CD86, whereas SNs contained higher amounts of IL-6 and CCL19 compared with control conditions. Gene-expression analyses on sorted cDCLPS or cDCP(I:C) conditioned pDCs confirmed the induction of several genes, including IL-6 and CCL19 and remarkably, several Notch target genes. Further studies using the γ-secretase/Notch inhibitor DAPT and soluble Notch ligands resulted in a significantly reduced expression of canonical Notch target genes in conditioned pDCs. DAPT treatment also hampered the secretion of CCL19 (but not of IL-6) by cDCLPS conditioned pDCs. These results reveal the involvement of γ-secretase-mediated mechanisms, including the Notch pathway, in the cell contact-dependent communication between human DC subsets. The resulting partial activation of pDCs after encountering with mature cDCs endows pDCs with an accessory function that may contribute to T cell recruitment and activation. © Society for Leukocyte Biology.
Original languageEnglish
Pages (from-to)133-143
JournalJournal of Leukocyte Biology
Volume92
Issue number1
DOIs
Publication statusPublished - 1 Jul 2012

Keywords

  • γ-secretase
  • CCL19
  • Cooperation
  • Dendritic cells
  • Human
  • Notch

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