. L'élimination de pathogènes extracellulaires dépendante de l'intervention des lymphocytes Th17 serait donc opérationnelle chez le nouveau-né. De part le rôle de l'IL-27 dans l'inhibition des réponses de type Th2, le défaut de production de cette cytokine pourrait également contribuer au développement d'allergie en début de vie.
4.2 Implications pour les stratégies vaccinales
Un des défis actuels de la vaccinologie est de développer des vaccins efficaces dès la naissance et permettant une protection de longue durée par l'administration d'une dose unique. L’immunisation précoce des nourrissons représente une stratégie applicable pour diminuer la mortalité importante due aux maladies infectieuses en bas âge. Dans ce contexte, les stratégies vaccinales doivent tenir compte de l’immaturité du système immunitaire néonatal. Nos recherches contribuent à l'effort indispensable visant à définir les bases moléculaires et cellulaires de l’immaturité immunologique du nouveau-né.
Le concept de base du vaccin est de cibler le système immunitaire de manière à induire une réponse adaptative, incluant la production d'anticorps par les lymphocytes B et les réponses cellulaires médiées par les cellules T spécifiques de l'antigène, permettant d'éviter une infection ou de réduire la pathologie associée à celle-ci. L'adjuvant présent dans les vaccins est indispensable pour activer de manière efficace les cellules du système immunitaire et fournir une immunogénicité optimale de l'antigène. Les DCs sont les principales cibles cellulaires des nouveaux vaccins car elles constituent le lien entre l’immunité innée et le développement des réponses immunes adaptatives. Les nouveaux adjuvants doivent donc être capables d'activer les cellules dendritiques du nouveau-né de manière efficace. Plusieurs ligands des TLRs ont été choisis pour jouer le rôle d'adjuvants
dans les nouveaux vaccins. Ce choix n'est pas anodin étant donné que ces ligands ciblent principalement les DCs et induisent des réponses de type Th1. Ainsi, le MPL (monophosphoryl lipid), ligand TLR4, est déjà utilisé dans les vaccins contre l'hépatite B (FENdrix) et contre le papillomavirus humain de type 16/18 (HPV, Cervarix). Le MPL mais aussi l'imiquimod, ligand de TLR7/8 et la flagélline, ligand TLR5, semblent prometteurs pour améliorer la réponse immune notamment dans le cadre d'un vaccin contre
Plasmodium falciparum 519-521.
Le ligand qui servira d'adjuvant dans les stratégies vaccinales du nouveau-né doit être capable de contourner les déficiences intrinsèques des cellules dendritiques néonatales, notamment le défaut d'activation d'IRF3 et de production des IFNs de type I, afin d’induire la synthèse de cytokines pro-Th1 telles que l'IL-12 et l'IL-27. A côté des ligands de TLR3 et TLR4, la production d'IFNβ est induite par l'engagement des récepteurs cytosoliques RIG-1 et MDA5. Cependant, les différentes études réalisées dans le but d'identifier les facteurs de transcription participant à la voie de signalisation activée par ces récepteurs ont démontré le rôle déterminant d'IRF3. Il est donc concevable que le défaut d'activation d'IRF3 et le défaut de production d'IFNβ subséquent observés suite à l'engagement de TLR3 et TLR4, le sera également lors de l'activation de RIG-1 et MDA5. Il a été montré que suite à une infection par le cytomégalovirus, les DCs myéloïdes du nouveau-né sont capables de produire des IFNαs et de nombreux gènes IFN-dépendants de manière comparable aux DCs myéloïdes isolées à partir de sang d’adulte 522. Ces données suggèrent donc que certaines voies d’activation menant à la production d’IFNs de type I sont fonctionnelles chez le nouveau-né. L’identification des facteurs de transcription impliqués dans ces voies de signalisation serait utile pour induire la production d’IL-27 par les DCs myéloïdes du nouveau-né. En effet, nos résultats indiquent que la production d'IL-27 par les DCs, en réponse au polyI:C, est moins dépendante d'IRF3 qu'en réponse au LPS. C'est principalement la formation du complexe ISGF3 suite à l’action des IFNs de type I qui est essentielle à l'expression de la p28. La synthèse d'IL-12 et d'IL-27 est également amplifiée par la présence d'IFNγ. Une autre possibilité serait donc d'induire la sécrétion d’IFNγ par des cellules du système immunitaire inné tels que les lymphocytes Tγδ, les cellules NK ou les cellules NKT qui sont fonctionnelles pour la production de cette cytokine chez le nouveau-né 519,520,523-525.
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