Dectin-1 activation unlocks IL12A expression and reveals the TH1 potency of neonatal dendritic cells - 06/11/15
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.
Le texte complet de cet article est disponible en PDF.Key words : Newborn, dendritic cells, TH1, adjuvant, C-type lectin receptor, Toll-like receptor, innate immunity
Abbreviations used : CARD9, CFU, CLR, Ct, DC, DZN, FACS, HBV, IFA, ITAM, mDC, moDC, MPLA, OVA, pDC, PIC, qPCR, Syk, TLR, WGP
Plan
| Supported by an ANR grant (ANR 09-MIEN-017) and Fondation pour la Recherche Médicale (grant no. DEQ20120323719). This study also received funding from the French Government's Investissement d'Avenir program, Laboratoire d'Excellence “Integrative Biology of Emerging Infectious Diseases” (grant no. ANR-10-LABX-62-IBEID). S.L. was supported by ANR and the European Commission FP7 ADITEC program (HEALTH-F4-2011-280873). D.Z. was supported by DIM Malinf and Region Île de France. |
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| Disclosure of potential conflict of interest: P. Tissieres has received consultancy fees from Biomerieux and has received research support from the Merieux Foundation. R. Lo-Man has received research support from Fondation pour la recherche Medicale, the French National Agency for Research, the European Commmission, and Region Ile de France. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 136 - N° 5
P. 1355 - novembre 2015 Retour au numéro
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