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Inflammation-Driven Reprogramming of CD4.sup.+Foxp3.sup.+ Regulatory T Cells into Pathogenic Th1/Th17 T Effectors Is Abrogated by mTOR Inhibition in vivo
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Inflammation-Driven Reprogramming of CD4.sup.+Foxp3.sup.+ Regulatory T Cells into Pathogenic Th1/Th17 T Effectors Is Abrogated by mTOR Inhibition in vivo
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Inflammation-Driven Reprogramming of CD4.sup.+Foxp3.sup.+ Regulatory T Cells into Pathogenic Th1/Th17 T Effectors Is Abrogated by mTOR Inhibition in vivo
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Journal Article
Inflammation-Driven Reprogramming of CD4.sup.+Foxp3.sup.+ Regulatory T Cells into Pathogenic Th1/Th17 T Effectors Is Abrogated by mTOR Inhibition in vivo
2012
Overview
While natural CD4.sup.+ Foxp3.sup.+ regulatory T (nT.sub.REG) cells have long been viewed as a stable and distinct lineage that is committed to suppressive functions in vivo, recent evidence supporting this notion remains highly controversial. We sought to determine whether Foxp3 expression and the nT.sub.REG cell phenotype are stable in vivo and modulated by the inflammatory microenvironment. Here, we show that Foxp3.sup.+ nT.sub.REG cells from thymic or peripheral lymphoid organs reveal extensive functional plasticity in vivo. We show that nT.sub.REG cells readily lose Foxp3 expression, destabilizing their phenotype, in turn, enabling them to reprogram into Th1 and Th17 effector cells. nT.sub.REG cell reprogramming is a characteristic of the entire Foxp3.sup.+ nT.sub.REG population and the stable Foxp3.sup.NEG T.sub.REG cell phenotype is associated with a methylated foxp3 promoter. The extent of nT.sub.REG cell reprogramming is modulated by the presence of effector T cell-mediated signals, and occurs independently of variation in IL-2 production in vivo. Moreover, the gut microenvironment or parasitic infection favours the reprogramming of Foxp3.sup.+ T.sub.REG cells into effector T cells and promotes host immunity. IL-17 is predominantly produced by reprogrammed Foxp3.sup.+ nT.sub.REG cells, and precedes Foxp3 down-regulation, a process accentuated in mesenteric sites. Lastly, mTOR inhibition with the immunosuppressive drug, rapamycin, stabilizes Foxp3 expression in T.sub.REG cells and strongly inhibits IL-17 but not ROR[gamma]t expression in reprogrammed Foxp3.sup.- T.sub.REG cells. Overall, inflammatory signals modulate mTOR signalling and influence the stability of the Foxp3.sup.+ nT.sub.REG cell phenotype.
Publisher
Public Library of Science
Subject
