Inflammation-driven reprogramming of CD4+Foxp3+ regulatory T cells into pathogenic Th1/Th17 T effectors is abrogated by mTOR inhibition in vivo

Abstract

While natural CD4+Foxp3+ regulatory T (nTREG) 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 nTREG cell phenotype are stable in vivo and modulated by the inflammatory microenvironment. Here, we show that Foxp3+ nTREG cells from thymic or peripheral lymphoid organs reveal extensive functional plasticity in vivo. We show that nTREG cells readily lose Foxp3 expression, destabilizing their phenotype, in turn, enabling them to reprogram into Th1 and Th17 effector cells. nTREG cell reprogramming is a characteristic of the entire Foxp3+ nTREG population and the stable Foxp3NEG TREG cell phenotype is associated with a methylated foxp3 promoter. The extent of nTREG 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+ TREG cells into effector T cells and promotes host immunity. IL-17 is predominantly produced by reprogrammed Foxp3+ nTREG cells, and precedes Foxp3 down-regulation, a process accentuated in mesenteric sites. Lastly, mTOR inhibition with the immunosuppressive drug, rapamycin, stabilizes Foxp3 expression in TREG cells and strongly inhibits IL-17 but not RORct expression in reprogrammed Foxp32 TREG cells. Overall, inflammatory signals modulate mTOR signalling and influence the stability of the Foxp3+ nTREG cell phenotype. Citation: Yurchenko E, Shio MT, Huang TC, Da Silva Martins M, Szyf M, et al. (2012) Inflammation-Driven Reprogramming of CD4+Foxp3+ Regulatory T Cells into Pathogenic Th1/Th17 T Effectors Is Abrogated by mTOR Inhibition in vivo. PLoS ONE 7(4): e35572. doi:10.1371/journal.pone.0035572 Editor: Derya Unutmaz, New York University, United States of America Received December 19, 2011; Accepted March 20, 2012; Published April 24, 2012 Copyright:  2012 Yurchenko et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors acknowledge the financial support of the Canadian Institutes for Health Research (MOP 67211 and MOP 84037 to C.A.P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript Competing Interests: The authors have declared that no competing interests exist. * E-mail: Ciro.piccirillo@mcgill.ca

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