Elusive Modes of Foxp3 Activity in Versatile Regulatory T Cells

Overview

Journal Front Immunol

Date 2025 Jan 30

PMID 39882241

Authors

Minghong He

Yongqiang Feng

Affiliations

Soon will be listed here.

Abstract

Foxp3-expressing CD4 regulatory T (Treg) cells play a crucial role in suppressing autoimmunity, tolerating food antigens and commensal microbiota, and maintaining tissue integrity. These multifaceted functions are guided by environmental cues through interconnected signaling pathways. Traditionally, Treg fate and function were believed to be statically determined by the forkhead box protein Foxp3 that directly binds to DNA. However, this model has not been rigorously tested in physiological and pathological conditions where Treg cells adapt their function in response to environmental cues, raising questions about the contribution of Foxp3-dependent gene regulation to their versatility. Recent research indicates that Foxp3 primarily functions as a transcriptional cofactor, whose chromatin interaction is influenced by other DNA-binding proteins that respond to cell activation, stimulation, or differentiation. This new perspective offers an opportunity to reevaluate Foxp3's activity modes in diverse biological contexts. By exploring this paradigm, we aim to unravel the fundamental principles of Treg cell biology.

References

Ciofani M, Madar A, Galan C, Sellars M, Mace K, Pauli F . A validated regulatory network for Th17 cell specification. Cell. 2012; 151(2):289-303. PMC: 3503487. DOI: 10.1016/j.cell.2012.09.016. View

Rudra D, deRoos P, Chaudhry A, Niec R, Arvey A, Samstein R . Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat Immunol. 2012; 13(10):1010-9. PMC: 3448012. DOI: 10.1038/ni.2402. View

Mishra S, Liao W, Liu Y, Yang M, Ma C, Wu H . TGF-β and Eomes control the homeostasis of CD8+ regulatory T cells. J Exp Med. 2020; 218(1). PMC: 7527976. DOI: 10.1084/jem.20200030. View

Wohlfert E, Grainger J, Bouladoux N, Konkel J, Oldenhove G, Hager Ribeiro C . GATA3 controls Foxp3⁺ regulatory T cell fate during inflammation in mice. J Clin Invest. 2011; 121(11):4503-15. PMC: 3204837. DOI: 10.1172/JCI57456. View

Arvey A, van der Veeken J, Samstein R, Feng Y, Stamatoyannopoulos J, Rudensky A . Inflammation-induced repression of chromatin bound by the transcription factor Foxp3 in regulatory T cells. Nat Immunol. 2014; 15(6):580-587. PMC: 4112080. DOI: 10.1038/ni.2868. View

Rosser E, Mauri C . Regulatory B cells: origin, phenotype, and function. Immunity. 2015; 42(4):607-12. DOI: 10.1016/j.immuni.2015.04.005. View

Samstein R, Arvey A, Josefowicz S, Peng X, Reynolds A, Sandstrom R . Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell. 2012; 151(1):153-66. PMC: 3493256. DOI: 10.1016/j.cell.2012.06.053. View

Arpaia N, Green J, Moltedo B, Arvey A, Hemmers S, Yuan S . A Distinct Function of Regulatory T Cells in Tissue Protection. Cell. 2015; 162(5):1078-89. PMC: 4603556. DOI: 10.1016/j.cell.2015.08.021. View

Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson S . PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature. 2012; 486(7404):549-53. PMC: 3387339. DOI: 10.1038/nature11132. View

10.

Munoz-Rojas A, Wang G, Benoist C, Mathis D . Adipose-tissue regulatory T cells are a consortium of subtypes that evolves with age and diet. Proc Natl Acad Sci U S A. 2024; 121(4):e2320602121. PMC: 10823167. DOI: 10.1073/pnas.2320602121. View

11.

Iwata A, Durai V, Tussiwand R, Briseno C, Wu X, Grajales-Reyes G . Quality of TCR signaling determined by differential affinities of enhancers for the composite BATF-IRF4 transcription factor complex. Nat Immunol. 2017; 18(5):563-572. PMC: 5401770. DOI: 10.1038/ni.3714. View

12.

Oldenhove G, Bouladoux N, Wohlfert E, Hall J, Chou D, Dos Santos L . Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity. 2009; 31(5):772-86. PMC: 2814877. DOI: 10.1016/j.immuni.2009.10.001. View

13.

Ohnmacht C, Park J, Cording S, Wing J, Atarashi K, Obata Y . MUCOSAL IMMUNOLOGY. The microbiota regulates type 2 immunity through RORγt⁺ T cells. Science. 2015; 349(6251):989-93. DOI: 10.1126/science.aac4263. View

14.

Van Gool F, Nguyen M, Mumbach M, Satpathy A, Rosenthal W, Giacometti S . A Mutation in the Transcription Factor Foxp3 Drives T Helper 2 Effector Function in Regulatory T Cells. Immunity. 2019; 50(2):362-377.e6. PMC: 6476426. DOI: 10.1016/j.immuni.2018.12.016. View

15.

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

16.

Itahashi K, Irie T, Yuda J, Kumagai S, Tanegashima T, Lin Y . BATF epigenetically and transcriptionally controls the activation program of regulatory T cells in human tumors. Sci Immunol. 2022; 7(76):eabk0957. DOI: 10.1126/sciimmunol.abk0957. View

17.

Cosmi L, Liotta F, Lazzeri E, Francalanci M, Angeli R, Mazzinghi B . Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes. Blood. 2003; 102(12):4107-14. DOI: 10.1182/blood-2003-04-1320. View

18.

Bandukwala H, Wu Y, Feuerer M, Chen Y, Barboza B, Ghosh S . Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells. Immunity. 2011; 34(4):479-91. PMC: 3085397. DOI: 10.1016/j.immuni.2011.02.017. View

19.

Zheng Y, Josefowicz S, Kas A, Chu T, Gavin M, Rudensky A . Genome-wide analysis of Foxp3 target genes in developing and mature regulatory T cells. Nature. 2007; 445(7130):936-40. DOI: 10.1038/nature05563. View

20.

van der Veeken J, Glasner A, Zhong Y, Hu W, Wang Z, Bou-Puerto R . The Transcription Factor Foxp3 Shapes Regulatory T Cell Identity by Tuning the Activity of trans-Acting Intermediaries. Immunity. 2020; 53(5):971-984.e5. PMC: 8363055. DOI: 10.1016/j.immuni.2020.10.010. View