Plasmacytoid dendritic cell dynamics tune interferon-alfa production in SIV-infected cynomolgus macaques

PLoS Pathog. 2014 Jan 30;10(1):e1003915. doi: 10.1371/journal.ppat.1003915. eCollection 2014 Jan.

Abstract

IFN-I production is a characteristic of HIV/SIV primary infections. However, acute IFN-I plasma concentrations rapidly decline thereafter. Plasmacytoid dendritic cells (pDC) are key players in this production but primary infection is associated with decreased responsiveness of pDC to TLR 7 and 9 triggering. IFNα production during primary SIV infection contrasts with increased pDC death, renewal and dysfunction. We investigated the contribution of pDC dynamics to both acute IFNα production and the rapid return of IFNα concentrations to pre-infection levels during acute-to-chronic transition. Nine cynomolgus macaques were infected with SIVmac251 and IFNα-producing cells were quantified and characterized. The plasma IFN-I peak was temporally associated with the presence of IFNα(+) pDC in tissues but IFN-I production was not detectable during the acute-to-chronic transition despite persistent immune activation. No IFNα(+) cells other than pDC were detected by intracellular staining. Blood-pDC and peripheral lymph node-pDC both lost IFNα(-) production ability in parallel. In blood, this phenomenon correlated with an increase in the counts of Ki67(+)-pDC precursors with no IFNα production ability. In tissues, it was associated with increase of both activated pDC and KI67(+)-pDC precursors, none of these being IFNα(+) in vivo. Our findings also indicate that activation/death-driven pDC renewal rapidly blunts acute IFNα production in vivo: pDC sub-populations with no IFNα-production ability rapidly increase and shrinkage of IFNα production thus involves both early pDC exhaustion, and increase of pDC precursors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dendritic Cells / immunology*
  • Dendritic Cells / pathology
  • Interferon-alpha / immunology
  • Lymph Nodes / immunology
  • Macaca fascicularis
  • Plasma Cells / immunology*
  • Plasma Cells / pathology
  • Simian Acquired Immunodeficiency Syndrome / immunology*
  • Simian Acquired Immunodeficiency Syndrome / pathology
  • Simian Immunodeficiency Virus / immunology*
  • Toll-Like Receptor 7 / immunology
  • Toll-Like Receptor 9 / immunology

Substances

  • Interferon-alpha
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9

Grant support

This work was supported by the French National Agency for AIDS Research and Viral Hepatitis-(ANRS; www.anrs.fr). TB was funded by the PhD program for life sciences of the CEA (Irtélis-INSTN) and SD was supported by a postdoctoral fellowship from the ANRS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.