Search

Neonatal immune cells have long been considered as immature versions of their adult counterparts, but overwhelming evidence suggests that they are as potent as adult cells to mount a protective response under specific circumstances. Rather, they are biased towards immunosuppressive mechanisms which correspond to the physiological demands of this time window. Indeed, neonates require to protect against infection but in the meantime, avoid alloimmune reaction, prevent Th1-mediated rejection and allow the commensal microbial colonization. This unique neonatal immune system, defined by a bias against Th1 cells polarizing cytokines, makes newborns more vulnerable to pathogenic infection with impaired immune responses to most vaccines and increased susceptibility to develop Th2-type inflammatory disorders such as allergies. Given the antigen inexperienced adaptive immunity, neonates rely on their innate immune system to confer protection but due to cell intrinsic hyperresponsiveness, frustrating efforts have been made to protect this vulnerable population. Recently, a lot of attention has focused on the first exposure to commensals that can activate innate immunity and potentially accelerate the neonatal maturation process. However, the mechanistic basis of the crosstalk between gut microbiota and immune system in newborns is poorly defined.To better understand how exogenous factors such as the microbiota prime the neonatal innate cells, we first assess the importance of commensal exposure on splenic and pulmonary conventional dendritic cells, which represent the bridge between innate and adaptive responses. In the neonatal spleen, the main subset is type 1 conventional dendritic cell precursors that have the particularity to produce the anti inflammatory cytokine IL-10, which limits Th1 responses as well as cytotoxic responses and thus maintain a tolerogenic environment. We report that the first exposure to microbiota induces a myeloid TNF secretion that drives the diffe, Le système immunitaire néonatale est associé au maintien d’un équilibre entre tolérance et protection afin de protéger l’hôte contre les infections, éviter les réactions allo immunes et permettre la colonisation microbienne commensale. Le début de vie est donc caractérisé par une susceptibilité accrue aux infections et aux réactions allergiques ainsi qu’une faible réponse vaccinale. Récemment, il a été mis en évidence que la colonisation du microbiote permet le développement du système immunitaire. Cependant, le mécanisme d'interaction entre le microbiote intestinal et le système immunitaire des nouveau-nés est mal défini.Dans un premier temps, nous avons démontré que la première exposition aux bactéries commensales induit une sécrétion de TNF par les cellules myéloïdes qui permet la différenciation et la maturation fonctionnelle des cellules dendritiques conventionnelles spléniques, en inhibant leur production d’IL-10 et en augmentant leur production d'IL-12p40. En outre, la colonisation du microbiote intestinal au début de la vie exerce également un effet à distance sur l'immunité pulmonaire en régulant positivement la fréquence des cellules dendritiques conventionnelles pulmonaires ainsi que des macrophages interstitiels en début de vie.Dans un second temps, nous avons mis en évidence que la supplémentation maternelle en probiotique Lactobacillus rhamnosus prévient l'asthme de type Th2 dans la progéniture en inhibant la maturation des cellules dendritiques conventionnelles pulmonaires et la polarisation ultérieure des cellules T contre les allergènes inhalés. Contre les allergènes systémiques, la prévention des réponses immunitaires de type 2 se produit en induisant la différentiation et la maturation fonctionnelle des cellules dendritiques conventionnelles spléniques qui favorisent alors une polarisation Th1, inhibant ainsi la polarisation des cellules T régulatrices. Par ailleurs, nous avons démontré que ce phénomène est dépendant des immunoglobulines G materne, Doctorat en Sciences biomédicales et pharmaceutiques (Médecine), info:eu-repo/semantics/nonPublished

Induction of immune protection against pathogens is particularly crucial during the neonatal period dominated by anti-inflammatory and tolerance immunity. The preclinical study was carried out to determine whether environmental factors such as microbiota may influence early life immunity by impacting the development and the functional maturation of precursors of type 1 conventional dendritic cells (pre-cDC1), endowed with regulatory properties., info:eu-repo/semantics/published

AU-rich element (ARE)-mediated mRNA decay represents a key mechanism to avoid excessive production of inflammatory cytokines. Tristetraprolin (TTP, encoded by Zfp36) is a major ARE-binding protein, since Zfp36−/− mice develop a complex multiorgan inflammatory syndrome that shares many features with spondyloarthritis. The role of TTP in intestinal homeostasis is not known. Herein, we show that Zfp36−/− mice do not develop any histological signs of gut pathology. However, they display a clear increase in intestinal inflammatory markers and discrete alterations in microbiota composition. Importantly, oral antibiotic treatment reduced both local and systemic joint and skin inflammation. We further show that absence of overt intestinal pathology is associated with local expansion of regulatory T cells. We demonstrate that this is related to increased vitamin A metabolism by gut dendritic cells, and identify RALDH2 as a direct target of TTP. In conclusion, these data bring insights into the interplay between microbiota-dependent gut and systemic inflammation during immune-mediated disorders, such as spondyloarthritis., SCOPUS: ar.j, info:eu-repo/semantics/published