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

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Published in PLOS ONE. 2013, vol. 8, no. 12, p. e85302
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.
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PMID: 24376875
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Article (Published version) (643 Kb) - public document Free access
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Research group Centre de Vaccinologie et d'Immunologie néonatale (177)
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BELNOUE, Elodie et al. Functional limitations of plasmacytoid dendritic cells limit type I interferon, T cell responses and virus control in early life. In: PLOS ONE, 2013, vol. 8, n° 12, p. e85302. https://archive-ouverte.unige.ch/unige:35596

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Deposited on : 2014-04-09

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