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

Ageliki Tsagaratou*, Edahí González-Avalos, Sini Rautio, James P. Scott-Browne, Susan Togher, William A. Pastor, Ellen V. Rothenberg, Lukas Chavez, Harri Lähdesmäki, Anjana Rao

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

43 Citations (Scopus)

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).

Original languageEnglish
Pages (from-to)45-53
JournalNATURE IMMUNOLOGY
Volume18
Issue number1
DOIs
Publication statusPublished - 2017
MoE publication typeA1 Journal article-refereed

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    Tsagaratou, A., González-Avalos, E., Rautio, S., Scott-Browne, J. P., Togher, S., Pastor, W. A., ... Rao, A. (2017). TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells. NATURE IMMUNOLOGY, 18(1), 45-53. https://doi.org/10.1038/ni.3630