Dectin-1 activation unlocks IL12A expression and reveals the T_H1 potency of neonatal dendritic cells

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• 作者：Sé ; bastien Lemoine ; PhD^a ; ^b ; Barbara Jaron ; PhD^a ; ^b ; Sabrine Tabka ; MSc^a ; ^b ; Chourouk Ettreiki ; PhD^c ; ⁱ ; Edith Deriaud ; BSc^a ; ^b ; Dania Zhivaki ; MSc^a ; ^b ; ^d ; Camille Le Ray ; MD^e ; ^f ; Odile Launay ; MD ; PhD^f ; ^g ; Laleh Majlessi ; PhD^h ; Pierre Tissieres ; MD ; PhD^c ; ⁱ ; ^j ; Claude Leclerc ; PhD^a ; ^b ; Richard Lo-Man ; PhD^a ; ^b ; ^{richard.lo-man@pasteur.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Newborn ; dendritic cells ; TH1 ; adjuvant ; C-type lectin receptor ; Toll-like receptor ; innate immunity
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2015
• 出版时间：November 2015
• 年：2015
• 卷：136
• 期：5
• 页码：1355-1368.e15
• 全文大小：6403 K

文摘

Early life is characterized by a high susceptibility to infection and a T_H2-biased CD4 T-cell response to vaccines. Toll-like receptor (TLR) agonists are currently being implemented as new vaccine adjuvants for T_H1 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_H1 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-γ–producing T_H1 cells. In vivo a Dectin-1 agonist as adjuvant was sufficient to induce T_H1 responses after vaccination of neonatal mice.

Conclusion

Coactivation of neonatal moDCs through Dectin-1 allows TLR-mediated IL-12p70 secretion and T_H1 polarization of neonatal T cells. Dectin-1 agonists represent a promising T_H1 adjuvant for pediatric vaccination.