Functional limitations of plasmacytoid dendritic cells limit type I interferon, T cell responses and virus control in early life

PLoS One. 2013 Dec 23;8(12):e85302. doi: 10.1371/journal.pone.0085302. eCollection 2013.

Abstract

Infant mortality from viral infection remains a major global health concern: viruses causing acute infections in immunologically mature hosts often follow a more severe course in early life, with prolonged or persistent viral replication. Similarly, the WE strain of lymphocytic choriomeningitis virus (LCMV-WE) causes acute self-limiting infection in adult mice but follows a protracted course in infant animals, in which LCMV-specific CD8⁺ T cells fail to expand and control infection. By disrupting type I IFNs signaling in adult mice or providing IFN-α supplementation to infant mice, we show here that the impaired early life T cell responses and viral control result from limited early type I IFN responses. We postulated that plasmacytoid dendritic cells (pDC), which have been identified as one major source of immediate-early IFN-I, may not exert adult-like function in vivo in the early life microenvironment. We tested this hypothesis by studying pDC functions in vivo during LCMV infection and identified a coordinated downregulation of infant pDC maturation, activation and function: despite an adult-like in vitro activation capacity of infant pDCs, the expression of the E2-2 pDC master regulator (and of critical downstream antiviral genes such as MyD88, TLR7/TLR9, NF-κB, IRF7 and IRF8) is downregulated in vivo at baseline and during LCMV infection. A similar pattern was observed in response to ssRNA polyU, a model ligand of the TLR7 viral sensor. This suggests that the limited T cell-mediated defense against early life viral infections is largely attributable to / regulated by infant pDC responses and provides incentives for novel strategies to supplement or stimulate immediate-early IFN-α responses.

MeSH terms

  • Age Factors
  • Analysis of Variance
  • Animals
  • Animals, Newborn
  • Arenaviridae Infections / immunology*
  • DNA Primers / genetics
  • Dendritic Cells / immunology*
  • Flow Cytometry
  • Interferon Type I / immunology*
  • Lymphocytic choriomeningitis virus / immunology*
  • Mice
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*

Substances

  • DNA Primers
  • Interferon Type I

Grant support

The authors have no support or funding to report.