Journal
NATURE IMMUNOLOGY
Volume 18, Issue 1, Pages 45-53Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3630
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Funding
- US National Institutes of Health [R01 AI44432, CA151535, R35CA210043]
- Leukemia and Lymphoma Society (Translation Research Project grant) [6187-12]
- Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research
- Albert Billings Ruddock Professorship at Caltech
- Cancer Research Institute (Irvington Institute postdoctoral fellowship)
- Fraternal Order of Eagles Fellow of the Damon Runyon Cancer Research Foundation [DRG-2069-11]
- National Science Foundation
- NATIONAL CANCER INSTITUTE [R35CA210043, R01CA151535] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [S10RR027366] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI044432] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [S10OD016262] Funding Source: NIH RePORTER
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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 MKT 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 MKT cell fate by ensuring their proper development and maturation and by suppressing aberrant proliferation mediated by the T cell antigen receptor (TCR).
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