Loss of TET2 and TET3 in Regulatory T Cells Unleashes Effector Function

Overview

Journal Nat Commun

Specialty Biology

Date 2019 May 3

PMID 31043609

Citations 90

Authors

Xiaojing Yue

Chan-Wang J Lio

Daniela Samaniego-Castruita

Xiang Li

Anjana Rao

Affiliations

Soon will be listed here.

Abstract

TET enzymes oxidize 5-methylcytosine to 5-hydroxymethylcytosine and other oxidized methylcytosines in DNA. Here we examine the role of TET proteins in regulatory T (Treg) cells. Tet2/3Foxp3 mice lacking Tet2 and Tet3 in Treg cells develop inflammatory disease, and Treg cells from these mice show altered expression of Treg signature genes and upregulation of genes involved in cell cycle, DNA damage and cancer. In littermate mice with severe inflammation, both CD4Foxp3 and CD4Foxp3 cells show strong skewing towards Tfh/Th17 phenotypes. Wild-type Treg cells in mixed bone marrow chimeras and in Tet2/3Foxp3 heterozygous female mice are unable to rescue the aberrant properties of Tet2/3Foxp3 Treg cells. Treg cells from Tet2/3Foxp3 mice tend to lose Foxp3 expression, and transfer of total CD4 T cells isolated from Tet2/3Foxp3 mice could elicit inflammatory disease in fully immunocompetent mice. Together, these data indicate that Tet2 and Tet3 are guardians of Treg cell stability and immune homeostasis.

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References

Iyer L, Tahiliani M, Rao A, Aravind L . Prediction of novel families of enzymes involved in oxidative and other complex modifications of bases in nucleic acids. Cell Cycle. 2009; 8(11):1698-710. PMC: 2995806. DOI: 10.4161/cc.8.11.8580. View

Zheng Y, Josefowicz S, Chaudhry A, Peng X, Forbush K, Rudensky A . Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature. 2010; 463(7282):808-12. PMC: 2884187. DOI: 10.1038/nature08750. View

Moran-Crusio K, Reavie L, Shih A, Abdel-Wahab O, Ndiaye-Lobry D, Lobry C . Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell. 2011; 20(1):11-24. PMC: 3194039. DOI: 10.1016/j.ccr.2011.06.001. View

Miyao T, Floess S, Setoguchi R, Luche H, Fehling H, Waldmann H . Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity. 2012; 36(2):262-75. DOI: 10.1016/j.immuni.2011.12.012. View

Ciccia A, Elledge S . The DNA damage response: making it safe to play with knives. Mol Cell. 2010; 40(2):179-204. PMC: 2988877. DOI: 10.1016/j.molcel.2010.09.019. View

Thornton A, Korty P, Tran D, Wohlfert E, Murray P, Belkaid Y . Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol. 2010; 184(7):3433-41. PMC: 3725574. DOI: 10.4049/jimmunol.0904028. View

Rubtsov Y, Rasmussen J, Chi E, Fontenot J, Castelli L, Ye X . Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008; 28(4):546-58. DOI: 10.1016/j.immuni.2008.02.017. View

Pierson W, Cauwe B, Policheni A, Schlenner S, Franckaert D, Berges J . Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3⁺ regulatory T cells. Nat Immunol. 2013; 14(9):959-65. PMC: 4128388. DOI: 10.1038/ni.2649. View

Yadav M, Louvet C, Davini D, Gardner J, Martinez-Llordella M, Bailey-Bucktrout S . Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J Exp Med. 2012; 209(10):1713-22, S1-19. PMC: 3457729. DOI: 10.1084/jem.20120822. View

10.

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

11.

Orlanski S, Labi V, Reizel Y, Spiro A, Lichtenstein M, Levin-Klein R . Tissue-specific DNA demethylation is required for proper B-cell differentiation and function. Proc Natl Acad Sci U S A. 2016; 113(18):5018-23. PMC: 4983829. DOI: 10.1073/pnas.1604365113. View

12.

Yue X, Trifari S, Aijo T, Tsagaratou A, Pastor W, Zepeda-Martinez J . Control of Foxp3 stability through modulation of TET activity. J Exp Med. 2016; 213(3):377-97. PMC: 4813667. DOI: 10.1084/jem.20151438. View

13.

Liao Y, Smyth G, Shi W . featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2013; 30(7):923-30. DOI: 10.1093/bioinformatics/btt656. View

14.

Zhou X, Bailey-Bucktrout S, Jeker L, Penaranda C, Martinez-Llordella M, Ashby M . Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol. 2009; 10(9):1000-7. PMC: 2729804. DOI: 10.1038/ni.1774. View

15.

Li X, Zheng Y . Regulatory T cell identity: formation and maintenance. Trends Immunol. 2015; 36(6):344-53. PMC: 4458194. DOI: 10.1016/j.it.2015.04.006. View

16.

Pastor W, Aravind L, Rao A . TETonic shift: biological roles of TET proteins in DNA demethylation and transcription. Nat Rev Mol Cell Biol. 2013; 14(6):341-56. PMC: 3804139. DOI: 10.1038/nrm3589. View

17.

Delgoffe G, Woo S, Turnis M, Gravano D, Guy C, Overacre A . Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature. 2013; 501(7466):252-6. PMC: 3867145. DOI: 10.1038/nature12428. View

18.

Yang R, Qu C, Zhou Y, Konkel J, Shi S, Liu Y . Hydrogen Sulfide Promotes Tet1- and Tet2-Mediated Foxp3 Demethylation to Drive Regulatory T Cell Differentiation and Maintain Immune Homeostasis. Immunity. 2015; 43(2):251-63. PMC: 4731232. DOI: 10.1016/j.immuni.2015.07.017. View

19.

He Y, Li B, Li Z, Liu P, Wang Y, Tang Q . Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science. 2011; 333(6047):1303-7. PMC: 3462231. DOI: 10.1126/science.1210944. View

20.

Meisel M, Hinterleitner R, Pacis A, Chen L, Earley Z, Mayassi T . Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature. 2018; 557(7706):580-584. PMC: 6238954. DOI: 10.1038/s41586-018-0125-z. View