Macrophage- and neutrophil-derived TNF-α instructs skin langerhans cells to prime antiviral immune responses.

Abstract

Dendritic cells are major APCs that can efficiently prime immune responses. However, the roles of skin-resident Langerhans cells (LCs) in eliciting immune responses have not been fully understood. In this study, we demonstrate for the first time, to our knowledge, that LCs in cynomolgus macaque skin are capable of inducing antiviral-specific immune responses in vivo. Targeting HIV-Gag or influenza hemagglutinin Ags to skin LCs using recombinant fusion proteins of anti-Langerin Ab and Ags resulted in the induction of the viral Ag-specific responses. We further demonstrated that such Ag-specific immune responses elicited by skin LCs were greatly enhanced by TLR ligands, polyriboinosinic polyribocytidylic acid, and R848. These enhancements were not due to the direct actions of TLR ligands on LCs, but mainly dependent on TNF-α secreted from macrophages and neutrophils recruited to local tissues. Skin LC activation and migration out of the epidermis are associated with macrophage and neutrophil infiltration into the tissues. More importantly, blocking TNF-α abrogated the activation and migration of skin LCs. This study highlights that the cross-talk between innate immune cells in local tissues is an important component for the establishment of adaptive immunity. Understanding the importance of local immune networks will help us to design new and effective vaccines against microbial pathogens.

• Authors: Olivier Epaulard, Lucille Adam, Candice Poux, Gerard Zurawski, Nina Salabert, Pierre Rosenbaum, Nathalie Dereuddre-Bosquet, Sandra Zurawski, Anne-Laure Flamar, Sangkon Oh, Gabrielle Romain, Catherine Chapon, Jacques Banchereau, Yves Lévy, Roger Le Grand, Frédéric Martinon
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 193 Issue 5 Pg. 2416-26 (Sep 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 25057007 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Association of Immunologists, Inc.

Chemical References

• Hemagglutinin Glycoproteins, Influenza Virus
• Imidazoles
• Tumor Necrosis Factor-alpha
• gag Gene Products, Human Immunodeficiency Virus
• Poly I
• resiquimod

Topics

• Adaptive Immunity (drug effects, physiology)
• Animals
• HIV-1 (immunology)
• Hemagglutinin Glycoproteins, Influenza Virus (immunology, pharmacology)
• Imidazoles (pharmacology)
• Influenza A virus (immunology)
• Langerhans Cells (immunology)
• Macaca mulatta
• Macrophages (immunology)
• Neutrophils (immunology)
• Poly I (pharmacology)
• Skin (immunology)
• Tumor Necrosis Factor-alpha (immunology)
• gag Gene Products, Human Immunodeficiency Virus (immunology, pharmacology)