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Nat Immunol. 2017 Jan;18(1):45-53. doi: 10.1038/ni.3630. Epub 2016 Nov 21.

TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells.

Author information

1
Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
2
Department of Computer Science, Aalto University School of Science, Aalto, Finland.
3
Sanford Consortium for Regenerative Medicine, La Jolla, California, USA.
4
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
5
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California, USA.

Abstract

TET proteins oxidize 5-methylcytosine in DNA to 5-hydroxymethylcytosine and other oxidation products. We found that simultaneous deletion of Tet2 and Tet3 in mouse CD4+CD8+ double-positive thymocytes resulted in dysregulated development and proliferation of invariant natural killer T cells (iNKT cells). Tet2-Tet3 double-knockout (DKO) iNKT cells displayed pronounced skewing toward the NKT17 lineage, with increased DNA methylation and impaired expression of genes encoding the key lineage-specifying factors T-bet and ThPOK. Transfer of purified Tet2-Tet3 DKO iNKT cells into immunocompetent recipient mice resulted in an uncontrolled expansion that was dependent on the nonclassical major histocompatibility complex (MHC) protein CD1d, which presents lipid antigens to iNKT cells. Our data indicate that TET proteins regulate iNKT cell fate by ensuring their proper development and maturation and by suppressing aberrant proliferation mediated by the T cell antigen receptor (TCR).

PMID:
27869820
PMCID:
PMC5376256
DOI:
10.1038/ni.3630
[Indexed for MEDLINE]
Free PMC Article

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