Foxp3 instability leads to the generation of pathogenic memory T cells in vivo

By Xuyu Zhou, Samantha Bailey-bucktrout, L. Jeker, C. Penaranda, M. Martínez‐Llordella, Meredith Ashby, M. Nakayama, Wendy L. Rosenthal, J. Bluestone. Nature Immunology, 2009

1,306 citations recorded by the source corpus.

Regulatory T cells (Treg cells) are central to the maintenance of immune homeostasis. However, little is known about the stability of Treg cells in vivo. In this study, we demonstrate that a substantial percentage of cells had transient or unstable expression of the transcription factor Foxp3. These 'exFoxp3' T cells had an activated-memory T cell phenotype and produced inflammatory cytokines. Moreover, exFoxp3 cell numbers were higher in inflamed tissues in autoimmune conditions. Adoptive transfer of autoreactive exFoxp3 cells led to the rapid onset of diabetes. Finally, analysis of the T cell receptor repertoire suggested that exFoxp3 cells developed from both natural and adaptive Treg cells. Thus, the generation of potentially autoreactive effector T cells as a consequence of Foxp3 instability has important implications for understanding autoimmune disease pathogenesis.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/8934653c4efe2bad08de7605d83340d1c82e8cbe

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Citations in the corpus

Extrathymically generated regulatory T cells control mucosal Th2 inflammation (2012, result): “However, the dynamics and stability of Foxp3 expression has been a controversial issue, with a number of studies favouring unstable Foxp3 expression in iT reg cell”
Peripheral CD4 T cell differentiation regulated by networks of cytokines and transcription factors (2010, background): “the expression of Th1, Th2, and Th17 master regulators may attain a certain threshold so that Foxp3 can no longer suppress the production of effector cytokines and such Tregs may convert into effector cells (180).”
Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo (2012, methodology): “Foxp3-GFP-Cre reporter mice have been previously described (Louvet et al., 2009; Zhou et al., 2009).”
Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis (2009, positive): “A study using a Foxp3 reporter lineage marker system has shown that there is some spontaneous loss of Foxp3 expression in vivo , which is enhanced in nonobese diabetic mice with autoimmune diseas”
Phenotypic and functional specialization of FOXP3+ regulatory T cells (2011, background): “Furthermore, the frequency of these 'ex-T Reg cells' was increased in the pancreatic islets of non-obese diabetic (NOD) mice, indicating that they may contribute to autoimmune patholog”
Regulatory T Cells and Foxp3 (2011, background): “The Foxp3GFP–ER–Cre allele combined with R26Y reporter allows for YFP tagging of a cohort of differentiated Treg cells and monitor maintenance of Foxp3 expression in these cells.”
IDO in the Tumor Microenvironment: Inflammation, Counter-regulation and Tolerance (2016, positive): “These destabilized Tregs may then reprogram into pro-inflammatory effector cells [90-92], which have been termed “ex-Tregs” [89, 93, 94].”
The Balance of Th17 versus Treg Cells in Autoimmunity (2018, background): “transferred, they induced diabetes and expressed proinflammatory cytokines (IFN-γ and IL-17), suggesting that they were activated memory cells [104].”
FOXP3+ regulatory T cells in the human immune system (2010, background): “Indeed, in mice, recent reports have highlighted the plasticity of T Reg cells towards effector T H 1, T H 2 or T H 17 cell phenotypes under pathological condition”
Development and maintenance of regulatory T cells. (2013, background): “…retinoic acids, rapamycin, and sphingosine 1-phosphate receptor agonist FTY720 (Battaglia et al., 2006; Hill et al., 2008; Mucida et al., 2007; Zhou et al., 2009a), and that several signaling pathways, including those of NFAT, Smad3, and the Nr4a family, are critical for inducing Foxp3…”
Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses (2010, positive): “Loss of Foxp3 in Treg cells resulted in the acquisition of the ability to produce proinflammatory cytokines, and cause tissue lesions in the absence of functional Treg cells (Williams and Rudensky, 2007; Zhou et al., 2009).”