title: Functional limitations of plasmacytoid dendritic cells limit type I interferon, T cell responses and virus control in early life.
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.
authors.affiliation: World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland.
authors.forename: Elodie
authors.initials: E
authors.lastname: Belnoue
authors.affiliation: World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland.
authors.forename: Paola
authors.initials: P
authors.lastname: Fontannaz
authors.affiliation: World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland.
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Rochat
authors.affiliation: World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland.
authors.forename: Chantal
authors.initials: C
authors.lastname: Tougne
authors.affiliation: World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bergthaler
authors.affiliation: World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland.
authors.forename: Paul-Henri
authors.initials: PH
authors.lastname: Lambert
authors.affiliation: World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Pinschewer
authors.affiliation: World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland.
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Siegrist
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001117:Arenaviridae Infections / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology*; D005434:Flow Cytometry; D007370:Interferon Type I / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D017931:DNA Primers; D007370:Interferon Type I