Abstract

Infection by Listeria monocytogenes (Lm) causes serious sepsis and meningitis leading to mortality in neonates. This work explored the ability of CD11chigh 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 CD11chighCD8alpha+ dendritic cells (DCs). We characterized a dominant functional Batf3-dependent precursor of CD11chigh DCs that is Clec9A+CD205+CD24+ but CD8alpha- 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+ CD8alpha- DCs, endowed with regulatory properties in early life that represents a valuable target to augment memory responses to vaccines.

This study was supported by the Fonds National de la Recherche Scientifique (FNRS, Belgium) and an Interuniversity Attraction Pole of the Belgian Federal Science Policy. DT and AK are sponsored by the FNRS. MHL, KS, and IC are supported by grants from the National Health and Medical Research Council of Australia, and their work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government Research Institute