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J Allergy Clin Immunol. 2015 Nov;136(5):1355-68.e1-15. doi: 10.1016/j.jaci.2015.02.030. Epub 2015 Apr 10.

Dectin-1 activation unlocks IL12A expression and reveals the TH1 potency of neonatal dendritic cells.

Author information

1
Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France; INSERM U1041, Paris, France.
2
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.
3
Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France; INSERM U1041, Paris, France; Université Paris Diderot, Paris, France.
4
APHP, Department of Obstetrics and Gynecology, Maternité Port Royal, Paris, France; Université Paris Descartes, Faculté de Médecine, Paris, France.
5
Université Paris Descartes, Faculté de Médecine, Paris, France; INSERM CIC1417, Paris, France.
6
Unité de Pathogénomique Mycobactérienne Intégrée, Institut Pasteur, Paris, France.
7
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.
8
Unité de Régulation Immunitaire et Vaccinologie, Institut Pasteur, Paris, France; INSERM U1041, Paris, France. Electronic address: richard.lo-man@pasteur.fr.

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.

CONCLUSION:

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.

KEYWORDS:

C-type lectin receptor; Newborn; T(H)1; Toll-like receptor; adjuvant; dendritic cells; innate immunity

PMID:
25865351
DOI:
10.1016/j.jaci.2015.02.030
[Indexed for MEDLINE]

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