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

被引：41

作者：

Lemoine, Sebastien ^{[1
,2
]}

Jaron, Barbara ^{[1
,2
]}

Tabka, Sabrine ^{[1
,2
]}

Ettreiki, Chourouk ^{[3
,9
]}

Deriaud, Edith ^{[1
,2
]}

Zhivaki, Dania ^{[1
,2
,4
]}

Le Ray, Camille ^{[5
,6
]}

Launay, Odile ^{[6
,7
]}

Majlessi, Laleh ^{[8
]}

Tissieres, Pierre ^{[3
,9
,10
]}

Leclerc, Claude ^{[1
,2
]}

Lo-Man, Richard ^{[1
,2
]}

机构：

[1] Inst Pasteur, Unite Regulat Immunitaire & Vaccinol, Paris, France

[2] INSERM U1041, Paris, France

[3] Hop Univ Paris Sud, AP HP, Unite Reanimat Pediat & Med Neonatale, Le Kremlin Bicetre, France

[4] Univ Paris Diderot, Paris, France

[5] Maternite Port Royal, AP HP, Dept Obstet & Gynecol, Paris, France

[6] Univ Paris 05, Fac Med, Paris, France

[7] INSERM CIC1417, Paris, France

[8] Inst Pasteur, Unite Pathogenom Mycobacterienne Integree, Paris, France

[9] Univ Paris 11, Inst Genet & Microbiol, UMR 8621, Grp Equipe Endotoxine Struct & Activite, F-91405 Orsay, France

[10] Univ Paris 11, Fac Med, Le Kremlin Bicetre, France

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2015年 / 136卷 / 05期

关键词：

Newborn; dendritic cells; T(H)1; adjuvant; C-type lectin receptor; Toll-like receptor; innate immunity; CD4(+) T-CELLS; CYTOKINE RESPONSES; GAMMA PRODUCTION; RECEPTOR; IMMUNITY; INNATE; RECOGNITION; AGONISTS; LIPOPOLYSACCHARIDE; ENGAGEMENT;

D O I：

10.1016/j.jaci.2015.02.030

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

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.

引用

页码：1355 / +

页数：29