A Multiply Redundant Genetic Switch 'locks In' the Transcriptional Signature of Regulatory T Cells

Overview

Journal Nat Immunol

Date 2012 Sep 11

PMID 22961053

Citations 163

Authors

Wenxian Fu

Ayla Ergun

Ting Lu

Jonathan A Hill

Sokol Haxhinasto

Marlys S Fassett

Roi Gazit

Stanley Adoro

Laurie Glimcher

Susan Chan

Philippe Kastner

Derrick Rossi

James J Collins

Diane Mathis

Christophe Benoist

Affiliations

Soon will be listed here.

Abstract

The transcription factor Foxp3 participates dominantly in the specification and function of Foxp3(+)CD4(+) regulatory T cells (T(reg) cells) but is neither strictly necessary nor sufficient to determine the characteristic T(reg) cell signature. Here we used computational network inference and experimental testing to assess the contribution of other transcription factors to this. Enforced expression of Helios or Xbp1 elicited distinct signatures, but Eos, IRF4, Satb1, Lef1 and GATA-1 elicited exactly the same outcome, acting in synergy with Foxp3 to activate expression of most of the T(reg) cell signature, including key transcription factors, and enhancing occupancy by Foxp3 at its genomic targets. Conversely, the T(reg) cell signature was robust after inactivation of any single cofactor. A redundant genetic switch thus 'locked in' the T(reg) cell phenotype, a model that would account for several aspects of T(reg) cell physiology, differentiation and stability.

Citing Articles

Tumor-derived colorectal cancer organoids induce a unique Treg cell population by directing CD4 T cell differentiation.

Revilla S, Frederiks C, Prekovic S, Mocholi E, Kranenburg O, Coffer P iScience. 2025; 28(2):111827.

PMID: 39995881 PMC: 11848486. DOI: 10.1016/j.isci.2025.111827.

Elusive modes of Foxp3 activity in versatile regulatory T cells.

He M, Feng Y Front Immunol. 2025; 15:1533823.

PMID: 39882241 PMC: 11774722. DOI: 10.3389/fimmu.2024.1533823.

Dynamic chromatin architecture identifies new autoimmune-associated enhancers for and novel genes regulating CD4+ T cell activation.

Pahl M, Sharma P, Thomas R, Thompson Z, Mount Z, Pippin J Elife. 2024; 13.

PMID: 39302339 PMC: 11418197. DOI: 10.7554/eLife.96852.

An integrated transcription factor framework for Treg identity and diversity.

Chowdhary K, Leon J, Mathis D, Benoist C Proc Natl Acad Sci U S A. 2024; 121(36):e2411301121.

PMID: 39196621 PMC: 11388289. DOI: 10.1073/pnas.2411301121.

Inferring upstream regulatory genes of FOXP3 in human regulatory T cells from time-series transcriptomic data.

Magni S, Sawlekar R, Capelle C, Tslaf V, Baron A, Zeng N NPJ Syst Biol Appl. 2024; 10(1):59.

PMID: 38811598 PMC: 11137136. DOI: 10.1038/s41540-024-00387-9.

References

Rahl P, Lin C, Seila A, Flynn R, McCuine S, Burge C . c-Myc regulates transcriptional pause release. Cell. 2010; 141(3):432-45. PMC: 2864022. DOI: 10.1016/j.cell.2010.03.030. View

Iliopoulos D, Hirsch H, Struhl K . An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell. 2009; 139(4):693-706. PMC: 2783826. DOI: 10.1016/j.cell.2009.10.014. View

Pan F, Yu H, Dang E, Barbi J, Pan X, Grosso J . Eos mediates Foxp3-dependent gene silencing in CD4+ regulatory T cells. Science. 2009; 325(5944):1142-6. PMC: 2859703. DOI: 10.1126/science.1176077. View

Komatsu N, Mariotti-Ferrandiz M, Wang Y, Malissen B, Waldmann H, Hori S . Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci U S A. 2009; 106(6):1903-8. PMC: 2644136. DOI: 10.1073/pnas.0811556106. View

Shi L, Wang R, Huang G, Vogel P, Neale G, Green D . HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med. 2011; 208(7):1367-76. PMC: 3135370. DOI: 10.1084/jem.20110278. View

Sakaguchi S, Yamaguchi T, Nomura T, Ono M . Regulatory T cells and immune tolerance. Cell. 2008; 133(5):775-87. DOI: 10.1016/j.cell.2008.05.009. View

Rubtsov Y, Niec R, Josefowicz S, Li L, Darce J, Mathis D . Stability of the regulatory T cell lineage in vivo. Science. 2010; 329(5999):1667-71. PMC: 4262151. DOI: 10.1126/science.1191996. View

Faith J, Hayete B, Thaden J, Mogno I, Wierzbowski J, Cottarel G . Large-scale mapping and validation of Escherichia coli transcriptional regulation from a compendium of expression profiles. PLoS Biol. 2007; 5(1):e8. PMC: 1764438. DOI: 10.1371/journal.pbio.0050008. View

Otsubo K, Kanegane H, Kamachi Y, Kobayashi I, Tsuge I, Imaizumi M . Identification of FOXP3-negative regulatory T-like (CD4(+)CD25(+)CD127(low)) cells in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Clin Immunol. 2011; 141(1):111-20. DOI: 10.1016/j.clim.2011.06.006. View

10.

Hill J, Hall J, Sun C, Cai Q, Ghyselinck N, Chambon P . Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi Cells. Immunity. 2008; 29(5):758-70. PMC: 3140207. DOI: 10.1016/j.immuni.2008.09.018. View

11.

Fontenot J, Rasmussen J, Williams L, Dooley J, Farr A, Rudensky A . Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity. 2005; 22(3):329-41. DOI: 10.1016/j.immuni.2005.01.016. View

12.

Beyer M, Thabet Y, Muller R, Sadlon T, Classen S, Lahl K . Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nat Immunol. 2011; 12(9):898-907. PMC: 3669688. DOI: 10.1038/ni.2084. View

13.

Battle A, Segal E, Koller D . Probabilistic discovery of overlapping cellular processes and their regulation. J Comput Biol. 2005; 12(7):909-27. DOI: 10.1089/cmb.2005.12.909. View

14.

Feuerer M, Hill J, Mathis D, Benoist C . Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol. 2009; 10(7):689-95. DOI: 10.1038/ni.1760. View

15.

Pittenger C, Kandel E . A genetic switch for long-term memory. C R Acad Sci III. 1998; 321(2-3):91-6. DOI: 10.1016/s0764-4469(97)89807-1. View

16.

Vignali D, Collison L, Workman C . How regulatory T cells work. Nat Rev Immunol. 2008; 8(7):523-32. PMC: 2665249. DOI: 10.1038/nri2343. View

17.

Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan A, Stroud J . FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell. 2006; 126(2):375-87. DOI: 10.1016/j.cell.2006.05.042. View

18.

Josefowicz S, Lu L, Rudensky A . Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol. 2012; 30:531-64. PMC: 6066374. DOI: 10.1146/annurev.immunol.25.022106.141623. View

19.

Dang E, Barbi J, Yang H, Jinasena D, Yu H, Zheng Y . Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011; 146(5):772-84. PMC: 3387678. DOI: 10.1016/j.cell.2011.07.033. View

20.

Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A . Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009; 15(8):930-9. PMC: 3115752. DOI: 10.1038/nm.2002. View