12 research outputs found
A threshold level of NFATc1 activity facilitates thymocyte differentiation and opposes notch-driven leukaemia development.
International audienceNFATc1 plays a critical role in double-negative thymocyte survival and differentiation. However, the signals that regulate Nfatc1 expression are incompletely characterized. Here we show a developmental stage-specific differential expression pattern of Nfatc1 driven by the distal (P1) or proximal (P2) promoters in thymocytes. Whereas, preTCR-negative thymocytes exhibit only P2 promoter-derived Nfatc1beta expression, preTCR-positive thymocytes express both Nfatc1beta and P1 promoter-derived Nfatc1alpha transcripts. Inducing NFATc1alpha activity from P1 promoter in preTCR-negative thymocytes, in addition to the NFATc1beta from P2 promoter impairs thymocyte development resulting in severe T-cell lymphopenia. In addition, we show that NFATc1 activity suppresses the B-lineage potential of immature thymocytes, and consolidates their differentiation to T cells. Further, in the pTCR-positive DN3 cells, a threshold level of NFATc1 activity is vital in facilitating T-cell differentiation and to prevent Notch3-induced T-acute lymphoblastic leukaemia. Altogether, our results show NFATc1 activity is crucial in determining the T-cell fate of thymocytes
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Restricting Microbial Exposure in Early Life Negates the Immune Benefits Associated with Gut Colonization in Environments of High Microbial Diversity
Background: Acquisition of the intestinal microbiota in early life corresponds with the development of the mucosal immune system. Recent work on caesarean-delivered infants revealed that early microbial composition is influenced by birthing method and environment. Furthermore, we have confirmed that early-life environment strongly influences both the adult gut microbiota and development of the gut immune system. Here, we address the impact of limiting microbial exposure after initial colonization on the development of adult gut immunity.
Methodology/Principal Findings: Piglets were born in indoor or outdoor rearing units, allowing natural colonization in the
immediate period after birth, prior to transfer to high-health status isolators. Strikingly, gut closure and morphological
development were strongly affected by isolator-rearing, independent of indoor or outdoor origins of piglets. Isolator-reared
animals showed extensive vacuolation and disorganization of the gut epithelium, inferring that normal gut closure requires
maturation factors present in maternal milk. Although morphological maturation and gut closure were delayed in isolatorreared
animals, these hard-wired events occurred later in development. Type I IFN, IL-22, IL-23 and Th17 pathways were
increased in indoor-isolator compared to outdoor-isolator animals during early life, indicating greater immune activation in
pigs originating from indoor environments reflecting differences in the early microbiota. This difference was less apparent
later in development due to enhanced immune activation and convergence of the microbiota in all isolator-reared animals.
This correlated with elevation of Type I IFN pathways in both groups, although T cell pathways were still more affected in
indoor-reared animals.
Conclusions/Significance: Environmental factors, in particular microbial exposure, influence expression of a large number
of immune-related genes. However, the homeostatic effects of microbial colonization in outdoor environments require
sustained microbial exposure throughout development. Gut development in high-hygiene environments negatively
impacts on normal succession of the gut microbiota and promotes innate immune activation which may impair immune
homeostasis