title: Dectin-1 activation unlocks IL12A expression and reveals the TH1 potency of neonatal dendritic cells.
abstract: BACKGROUND
  Early life is characterized by a high susceptibility to infection and a TH2-biased CD4 T-cell response to vaccines. Toll-like receptor (TLR) agonists are currently being implemented as new vaccine adjuvants for TH1 activation, but their translation to the field of pediatric vaccines is facing the impairment of neonatal innate TLR responses.
  
  
  OBJECTIVE
  We sought to analyze C-type lectin receptor pathways as an alternative or a coactivator to TLRs for neonatal dendritic cell activation for TH1 polarization.
  
  
  METHODS
  Neonatal monocyte-derived dendritic cells (moDCs) were exposed to various combinations of TLR agonists with or without Dectin-1 agonist. IL-12 and IL-23 responses were analyzed at the transcriptional and protein levels after stimulation. The intracellular pathways triggered by combined TLR plus Dectin-1 stimulation was determined by using pharmacologic inhibitors. The capacity of neonatal moDCs to differentiate naive CD4 TH cells was evaluated in cocultures with heterologous neonatal naive T cells. Curdlan was finally tested as an adjuvant within a subunit tuberculosis vaccine in neonatal mice.
  
  
  RESULTS
  Simultaneous coactivation through Dectin-1 and TLRs induced robust secretion of IL-12p70 by neonatal moDCs by unlocking transcriptional control on the p35 subunit of IL-12. Both the spleen tyrosine kinase and Raf-1 pathways were involved in this process, allowing differentiation of neonatal naive T cells toward IFN-γ-producing TH1 cells. In vivo a Dectin-1 agonist as adjuvant was sufficient to induce TH1 responses after vaccination of neonatal mice.
  
  
  CONCLUSIONS
  Coactivation of neonatal moDCs through Dectin-1 allows TLR-mediated IL-12p70 secretion and TH1 polarization of neonatal T cells. Dectin-1 agonists represent a promising TH1 adjuvant for pediatric vaccination.
authors: Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France; INSERM U1041, Paris, France.
authors: Sébastien
authors: S
authors: Lemoine
authors: Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France; INSERM U1041, Paris, France.
authors: Barbara
authors: B
authors: Jaron
authors: Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France; INSERM U1041, Paris, France.
authors: Sabrine
authors: S
authors: Tabka
authors: Unité de Réanimation Pédiatrique et Médecine Néonatale, AP-HP, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France; Groupe Equipe Endotoxine, Structures et Activité, Institut de Génétique et Microbiologie, UMR 8621, Université Paris Sud, Orsay, France.
authors: Chourouk
authors: C
authors: Ettreiki
authors: Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France; INSERM U1041, Paris, France.
authors: Edith
authors: E
authors: Deriaud
authors: Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France; INSERM U1041, Paris, France; Université Paris Diderot, Paris, France.
authors: Dania
authors: D
authors: Zhivaki
authors: APHP, Department of Obstetrics and Gynecology, Maternité Port Royal, Paris, France; Université Paris Descartes, Faculté de Médecine, Paris, France.
authors: Camille
authors: C
authors: Le Ray
authors: Université Paris Descartes, Faculté de Médecine, Paris, France; INSERM CIC1417, Paris, France.
authors: Odile
authors: O
authors: Launay
authors: Unité de Pathogénomique Mycobactérienne Intégrée, Institut Pasteur, Paris, France.
authors: Laleh
authors: L
authors: Majlessi
authors: Unité de Réanimation Pédiatrique et Médecine Néonatale, AP-HP, Hôpitaux Universitaires Paris-Sud, Le Kremlin Bicêtre, France; Groupe Equipe Endotoxine, Structures et Activité, Institut de Génétique et Microbiologie, UMR 8621, Université Paris Sud, Orsay, France; Faculté de Médecine, Université Paris Sud, Le Kremlin Bicêtre, France.
authors: Pierre
authors: P
authors: Tissieres
authors: Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France; INSERM U1041, Paris, France.
authors: Claude
authors: C
authors: Leclerc
authors: Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France; INSERM U1041, Paris, France. Electronic address: richard.lo-man@pasteur.fr.
authors: Richard
authors: R
authors: Lo-Man
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D018664:Interleukin-12 / Q000378:metabolism; D053765:Interleukin-12 Subunit p35; D037181:Lectins, C-Type / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014611:Vaccination; D000099181:Dectin-1
chemical_list: D000276:Adjuvants, Immunologic; D018664:Interleukin-12; D053765:Interleukin-12 Subunit p35; D037181:Lectins, C-Type; D019908:Proto-Oncogene Proteins c-raf; D000099181:Dectin-1
keywords: C-type lectin receptor; Newborn; T(H)1; Toll-like receptor; adjuvant; dendritic cells; innate immunity