Details

Autor(en) / Beteiligte

• Belnoue, E.
• Fontannaz, P.
• Rochat, A.-F.
• Lambert, P.-H.
• Pinschewer, D.
• Siegrist, C.-A.

Titel

P126 Defective type I IFNS production by plasmacytoid dendritic cells impairs T cell responses and virus control in early life

Ist Teil von

• Cytokine (Philadelphia, Pa.), 2012-09, Vol.59 (3), p.559-560

Ort / Verlag

Elsevier Ltd

Erscheinungsjahr

2012

Quelle

ScienceDirect

Beschreibungen/Notizen

• Cytopathic viruses causing acute infections in immunologically mature hosts often follow a prolonged course in early life, characterized by high viral titers maintained for several weeks. Accordingly, lymphocytic choriomeningitis virus (LCMV, WE strain) runs an acute course in adults but a protracted course in infant BALB/c mice, in which LCMV-specific CD8+ and CD4+ T cells fail to expand and control infection. To identify whether these defects were due to a dysfunction of innate immunity in infant mice, we analyzed early events of viral infection. Type I IFN production was assessed early after LCMV infection of infant (2-week-old) and adult mice by ELISA and real-time PCR. We compared viral titers (by plaque assay) and T cell responses (by FACS) of LCMV-infected infant/adult wild-type and infant/adult IFNAR−/− mice. Activation and function of plasmacytoid and conventional dendritic cells were analyzed by FACS and real-time PCR. The effect of supplementing recombinant IFN-alpha early after infection on viral control and T cell responses was investigated in infant mice. Our data showed an insufficient immediate-early IFN-alpha production in infant mice, which fails to support early viral control and the expansion of LCMV-specific T cells: disrupting IFNAR signaling in adult mice mimicked a protracted LCMV infection. Plasmacytoid dendritic cells (pDCs) which are the main source of type I IFNs in LCMV infection failed to acquire an activated phenotype in infant mice and displayed defective function in vivo upon LCMV infection reflected by the low expression of the central pDC transcription factor E2-2 and related genes (TLR7/9, IRF-7 and IRF-8), MyD88 and NF-KappaB. In contrast, the in vitro function of early life pDCs was normal suggesting an in vivo negative regulation of infant pDCs. Direct evidence of the contribution of type I IFNs for early life infection control was demonstrated by given exogenous IFN-alpha which restored virus control and CTL functionality in infant mice. In this study, we identify an age-specific down-regulation of multiple factors which are critical for the activation and function of pDCs and demonstrate that it is orchestrated by the E2-2 pDC regulator. We show that this down-regulation prevents the immediate-early burst of type I IFN and the early viral control and permanently impairs CD4+ and CD8+ T cell responses. The results suggest that early life pDC responses are tightly regulated in vivo, possibly to avoid potentially harmful inflammatory or autoimmune reactions. This concept offers novel opportunities for prevention and therapy of infectious complications in early life.