Dataset Information

IL-12p40/IL-10 Producing preCD8?/Clec9A+ Dendritic Cells Are Induced in Neonates upon Listeria monocytogenes Infection.

ABSTRACT: Infection by Listeria monocytogenes (Lm) causes serious sepsis and meningitis leading to mortality in neonates. This work explored the ability of CD11c(high) lineage DCs to induce CD8+ T-cell immune protection against Lm in mice before 7 days of life, a period symbolized by the absence of murine IL-12p70-producing CD11c(high)CD8?+ dendritic cells (DCs). We characterized a dominant functional Batf3-dependent precursor of CD11c(high) DCs that is Clec9A+CD205+CD24+ but CD8?- at 3 days of life. After Lm-OVA infection, these pre-DCs that cross-present Ag display the unique ability to produce high levels of IL-12p40 (not IL-12p70 nor IL-23), which enhances OVA-specific CD8+ T cell response, and regulatory IL-10 that limits OVA-specific CD8+ T cell response. Targeting these neonatal pre-DCs for the first time with a single treatment of anti-Clec9A-OVA antibody in combination with a DC activating agent such as poly(I:C) increased the protection against later exposure to the Lm-OVA strain. Poly(I:C) was shown to induce IL-12p40 production, but not IL-10 by neonatal pre-DCs. In conclusion, we identified a new biologically active precursor of Clec9A+ CD8?- DCs, endowed with regulatory properties in early life that represents a valuable target to augment memory responses to vaccines.

SUBMITTER: Torres D

PROVIDER: S-EPMC4830566 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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IL-12p40/IL-10 Producing preCD8α/Clec9A+ Dendritic Cells Are Induced in Neonates upon Listeria monocytogenes Infection.

Torres David D Köhler Arnaud A Delbauve Sandrine S Caminschi Irina I Lahoud Mireille H MH Shortman Ken K Flamand Véronique V

PLoS pathogens 20160413 4

Infection by Listeria monocytogenes (Lm) causes serious sepsis and meningitis leading to mortality in neonates. This work explored the ability of CD11c(high) lineage DCs to induce CD8+ T-cell immune protection against Lm in mice before 7 days of life, a period symbolized by the absence of murine IL-12p70-producing CD11c(high)CD8α+ dendritic cells (DCs). We characterized a dominant functional Batf3-dependent precursor of CD11c(high) DCs that is Clec9A+CD205+CD24+ but CD8α- at 3 days of life. Afte ...[more]

PMID: 27074026

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Project description:Listeria monocytogenes is a facultative intracellular bacterial pathogen that escapes from phagosomes and induces a robust adaptive immune response in mice, while mutants unable to escape phagosomes fail to induce a robust adaptive immune response and suppress the immunity to wildtype bacteria when co-administered. The capacity to suppress immunity can be reversed by blocking IL-10. In this study, we sought to understand the host receptors that lead to secretion of IL-10 in response to phagosome-confined L. monocytogenes (Δhly), with the ultimate goal of generating strains that fail to induce IL-10. We conducted a transposon screen to identify Δhly L. monocytogenes mutants that induced significantly more or less IL-10 secretion in bone marrow-derived macrophages (BMMs). A transposon insertion in lgt, which encodes phosphatidylglycerol-prolipoprotein diacylglyceryl transferase and is essential for the formation of lipoproteins, induced significantly reduced IL-10 secretion. Mutants with transposon insertions in pgdA and oatA, which encode peptidoglycan N-acetylglucosamine deacetylase and O-acetyltransferase, are sensitive to lysozyme and induced enhanced IL-10 secretion. A ΔhlyΔpgdAΔoatA strain was killed in BMMs and induced enhanced IL-10 secretion that was dependent on Unc93b1, a trafficking molecule required for signaling of nucleic acid-sensing TLRs. These data revealed that nucleic acids released by bacteriolysis triggered endosomal TLR-mediated IL-10 secretion. Secretion of IL-10 in response to infection with the parental strain was mostly TLR2-dependent, while IL-10 secretion in response to lysozyme-sensitive strains was dependent on TLR2 and Unc93b1. In mice, the IL-10 response to vacuole-confined L. monocytogenes was also dependent on TLR2 and Unc93b1. Co-administration of Δhly and ΔactA resulted in suppressed immunity in WT mice, but not in mice with mutations in Unc93b1. These data revealed that secretion of IL-10 in response to L. monocytogenes infection in vitro is mostly TLR2-dependent and immune suppression by phagosome-confined bacteria in vivo is mostly dependent on endosomal TLRs.

Dataset Information

IL-12p40/IL-10 Producing preCD8?/Clec9A+ Dendritic Cells Are Induced in Neonates upon Listeria monocytogenes Infection.

Publications

IL-12p40/IL-10 Producing preCD8α/Clec9A+ Dendritic Cells Are Induced in Neonates upon Listeria monocytogenes Infection.

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