期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 136, 期 5, 页码 1355-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2015.02.030
关键词
Newborn; dendritic cells; T(H)1; adjuvant; C-type lectin receptor; Toll-like receptor; innate immunity
资金
- ANR grant [ANR 09-MIEN-017]
- Fondation pour la Recherche Medicale [DEQ20120323719]
- French Government's Investissement d'Avenir program, Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases'' [ANR-10-LABX-62-IBEID]
- European Commission FP7 ADITEC program [HEALTH-F4-2011-280873]
- DIM Malinf
- Region Ile de France
- ANR
Background: Early life is characterized by a high susceptibility to infection and a T(H)2-biased CD4 T-cell response to vaccines. Toll-like receptor (TLR) agonists are currently being implemented as new vaccine adjuvants for T(H)1 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 T(H)1 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 T-H 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-gamma-producing T(H)1 cells. In vivo a Dectin-1 agonist as adjuvant was sufficient to induce T(H)1 responses after vaccination of neonatal mice. Conclusion: Coactivation of neonatal moDCs through Dectin-1 allows TLR-mediated IL-12p70 secretion and T(H)1 polarization of neonatal T cells. Dectin-1 agonists represent a promising T(H)1 adjuvant for pediatric vaccination.
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