title: TET proteins regulate the lineage specification and TCR-mediated expansion of iNKT cells.
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).
authors.affiliation: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Ageliki
authors.initials: A
authors.lastname: Tsagaratou
authors.affiliation: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Edahí
authors.initials: E
authors.lastname: González-Avalos
authors.affiliation: Department of Computer Science, Aalto University School of Science, Aalto, Finland.
authors.forename: Sini
authors.initials: S
authors.lastname: Rautio
authors.affiliation: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, California, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Scott-Browne
authors.affiliation: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Togher
authors.affiliation: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Pastor
authors.affiliation: Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA.
authors.forename: Ellen V
authors.identifier: 0000-0002-3901-347X
authors.initials: EV
authors.lastname: Rothenberg
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Chavez
authors.affiliation: Department of Computer Science, Aalto University School of Science, Aalto, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Lähdesmäki
authors.affiliation: Department of Signaling and Gene Expression, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.|Sanford Consortium for Regenerative Medicine, La Jolla, California, USA.|Department of Pharmacology and Moores Cancer Center, University of California at San Diego, La Jolla, California, USA.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D002478:Cells, Cultured; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000502:physiology*; D054504:Precursor Cells, T-Lymphoid / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D055610:Antigens, CD1d; D015704:CD4 Antigens; D016827:CD8 Antigens; D004268:DNA-Binding Proteins; D049308:Dioxygenases; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000098815:T-bet Transcription Factor; C584692:CD1d antigen, mouse; C497211:Zbtb7b protein, mouse; C551914:Tet2 protein, mouse; C551915:Tet3 protein, mouse