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Assessing the Development of Murine Plasmacytoid Dendritic Cells in Peyer's Patches Using Adoptive Transfer of Hematopoietic Progenitors
Published on: March 17, 2014
Functional limitations of plasmacytoid dendritic cells limit type I interferon, T cell responses and virus control in
Elodie Belnoue1, Paola Fontannaz1, Anne-Françoise Rochat1
1World Health Organization Collaborating Center for Vaccinology and Neonatal Immunology, Departments of Pathology-Immunology and Pediatrics, University of Geneva, Geneva, Switzerland.
Insights
Infant viral infections are severe due to limited early type I interferon responses. Impaired plasmacytoid dendritic cell function in infants hinders T cell control of viruses like LCMV.
Area of Science:
- Immunology
- Virology
- Neonatal Health
Background:
- Infant mortality from viral infections is a global concern, with viruses causing severe disease in early life.
- Lymphocytic choriomeningitis virus (LCMV) infection is self-limiting in adult mice but protracted in infants due to failed T cell responses.
Purpose of the Study:
- To investigate why early life T cell responses and viral control are impaired during viral infections.
- To determine if plasmacytoid dendritic cells (pDCs) function differently in infants compared to adults.
- To identify the molecular mechanisms behind infant pDC dysfunction.
Main Methods:
- Studied LCMV infection in infant and adult mice.
- Manipulated type I interferon (IFN) signaling in adult mice and supplemented IFN-α in infant mice.
- Analyzed pDC maturation, activation, and function in vivo and in vitro.
- Measured the expression of key regulatory and antiviral genes in pDCs.
Main Results:
- Impaired early life T cell responses and viral control are linked to limited early type I IFN responses.
- Infant pDCs exhibit coordinated downregulation of maturation, activation, and function in vivo, despite normal in vitro capacity.
- Expression of the pDC master regulator E2-2 and downstream antiviral genes is reduced in infant pDCs.
- This pattern is observed both at baseline and during LCMV infection, and in response to TLR7 ligand stimulation.
Conclusions:
- Limited T cell-mediated defense against early life viral infections is regulated by infant pDC responses.
- Infant pDC dysfunction, characterized by downregulated E2-2 and antiviral gene expression, contributes to severe viral infections in early life.
- Novel strategies to supplement or stimulate immediate-early IFN-α responses are warranted to improve infant antiviral defense.
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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