title: 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: French Alternative Energies and Atomic Energy Commission, Division of Immuno-Virology, Institute for Emerging Diseases and Innovative Therapies, Infectious Diseases Models for Innovative Therapies Center, 92265 Fontenay-aux-Roses, France; Unité Mixte de Recherche E1, Université Paris-Sud, 91405 Orsay, France; Vaccine Research Institute, 94010 Créteil, France; Infectious Diseases Unit, Grenoble University Hospital, 38043 Grenoble, France;
authors: Olivier
authors: O
authors: Epaulard
authors: French Alternative Energies and Atomic Energy Commission, Division of Immuno-Virology, Institute for Emerging Diseases and Innovative Therapies, Infectious Diseases Models for Innovative Therapies Center, 92265 Fontenay-aux-Roses, France; Unité Mixte de Recherche E1, Université Paris-Sud, 91405 Orsay, France; Vaccine Research Institute, 94010 Créteil, France;
authors: Lucille
authors: L
authors: Adam
authors: French Alternative Energies and Atomic Energy Commission, Division of Immuno-Virology, Institute for Emerging Diseases and Innovative Therapies, Infectious Diseases Models for Innovative Therapies Center, 92265 Fontenay-aux-Roses, France; Unité Mixte de Recherche E1, Université Paris-Sud, 91405 Orsay, France; Vaccine Research Institute, 94010 Créteil, France;
authors: Candice
authors: C
authors: Poux
authors: Vaccine Research Institute, 94010 Créteil, France; Baylor Institute for Immunology Research, Dallas, TX 75204;
authors: Gerard
authors: G
authors: Zurawski
authors: French Alternative Energies and Atomic Energy Commission, Division of Immuno-Virology, Institute for Emerging Diseases and Innovative Therapies, Infectious Diseases Models for Innovative Therapies Center, 92265 Fontenay-aux-Roses, France; Unité Mixte de Recherche E1, Université Paris-Sud, 91405 Orsay, France; Vaccine Research Institute, 94010 Créteil, France;
authors: Nina
authors: N
authors: Salabert
authors: French Alternative Energies and Atomic Energy Commission, Division of Immuno-Virology, Institute for Emerging Diseases and Innovative Therapies, Infectious Diseases Models for Innovative Therapies Center, 92265 Fontenay-aux-Roses, France; Unité Mixte de Recherche E1, Université Paris-Sud, 91405 Orsay, France; Vaccine Research Institute, 94010 Créteil, France;
authors: Pierre
authors: P
authors: Rosenbaum
authors: French Alternative Energies and Atomic Energy Commission, Division of Immuno-Virology, Institute for Emerging Diseases and Innovative Therapies, Infectious Diseases Models for Innovative Therapies Center, 92265 Fontenay-aux-Roses, France; Unité Mixte de Recherche E1, Université Paris-Sud, 91405 Orsay, France; Vaccine Research Institute, 94010 Créteil, France;
authors: Nathalie
authors: N
authors: Dereuddre-Bosquet
authors: Vaccine Research Institute, 94010 Créteil, France; Baylor Institute for Immunology Research, Dallas, TX 75204;
authors: Sandra
authors: S
authors: Zurawski
authors: Vaccine Research Institute, 94010 Créteil, France; Baylor Institute for Immunology Research, Dallas, TX 75204;
authors: Anne-Laure
authors: AL
authors: Flamar
authors: Baylor Institute for Immunology Research, Dallas, TX 75204;
authors: Sangkon
authors: S
authors: Oh
authors: French Alternative Energies and Atomic Energy Commission, Division of Immuno-Virology, Institute for Emerging Diseases and Innovative Therapies, Infectious Diseases Models for Innovative Therapies Center, 92265 Fontenay-aux-Roses, France; Unité Mixte de Recherche E1, Université Paris-Sud, 91405 Orsay, France; Vaccine Research Institute, 94010 Créteil, France;
authors: Gabrielle
authors: G
authors: Romain
authors: French Alternative Energies and Atomic Energy Commission, Division of Immuno-Virology, Institute for Emerging Diseases and Innovative Therapies, Infectious Diseases Models for Innovative Therapies Center, 92265 Fontenay-aux-Roses, France; Unité Mixte de Recherche E1, Université Paris-Sud, 91405 Orsay, France; Vaccine Research Institute, 94010 Créteil, France;
authors: Catherine
authors: C
authors: Chapon
authors: Vaccine Research Institute, 94010 Créteil, France; Baylor Institute for Immunology Research, Dallas, TX 75204;
authors: Jacques
authors: J
authors: Banchereau
authors: Vaccine Research Institute, 94010 Créteil, France; INSERM, Unité U955, 94010 Créteil, France; Universite Paris-Est, Faculte de Medecine, Unité Mixte de Recherche-S 955, 94010 Créteil, France; and.
authors: Yves
authors: Y
authors: Lévy
authors: French Alternative Energies and Atomic Energy Commission, Division of Immuno-Virology, Institute for Emerging Diseases and Innovative Therapies, Infectious Diseases Models for Innovative Therapies Center, 92265 Fontenay-aux-Roses, France; Unité Mixte de Recherche E1, Université Paris-Sud, 91405 Orsay, France; Vaccine Research Institute, 94010 Créteil, France;
authors: Roger
authors: R
authors: Le Grand
authors: French Alternative Energies and Atomic Energy Commission, Division of Immuno-Virology, Institute for Emerging Diseases and Innovative Therapies, Infectious Diseases Models for Innovative Therapies Center, 92265 Fontenay-aux-Roses, France; Unité Mixte de Recherche E1, Université Paris-Sud, 91405 Orsay, France; Vaccine Research Institute, 94010 Créteil, France; INSERM, 75014 Paris, France frederic.martinon@cea.fr.
authors: Frédéric
authors: F
authors: Martinon
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000502:physiology; D000818:Animals; D015497:HIV-1 / Q000276:immunology*; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D009980:Influenza A virus / Q000276:immunology*; D007801:Langerhans Cells / Q000276:immunology*; D008253:Macaca mulatta; D008264:Macrophages / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D011069:Poly I / Q000494:pharmacology; D012867:Skin / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology / Q000494:pharmacology*
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007093:Imidazoles; D014409:Tumor Necrosis Factor-alpha; D054301:gag Gene Products, Human Immunodeficiency Virus; D011069:Poly I; C402365:resiquimod