title: Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation.
abstract: The fidelity of T cell immunity depends greatly on coupling T cell receptor signaling with specific T cell effector functions. Here, we describe a chromatin-based mechanism that enables integration of TCR specificity into definite T cell lineage commitment. Using natural killer T cells (iNKT cell) as a model of a T cell subset that differentiates in response to specific TCR signaling, we identified a key role of histone H3 lysine 27 trimethylation (H3K27me3) in coupling iNKT cell TCR specificity with the generation of iNKT cells. We found that the Zbtb16/PLZF gene promoter that drives iNKT cell differentiation possesses a bivalent chromatin state characterized by the simultaneous presence of negative and positive H3K27me3 and H3K4me3 modifications. Depletion of H3K27me3 at the Zbtb16/PLZF promoter leads to uncoupling of iNKT cell development from TCR specificity and is associated with accumulation of iNKT-like CD4(+) cells that express a non-iNKT cell specific T cell repertoire. In turn, stabilization of H3K27me3 leads to a drastic reduction of the iNKT cell population. Our data suggest that H3K27me3 levels at the bivalent Zbtb16/PLZF gene define a threshold enabling precise coupling of TCR specificity to lineage commitment.
authors: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065 dobenem@rockefeller.edu tarakho@rockefeller.edu.
authors: Marc-Werner
authors: MW
authors: Dobenecker
authors: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors: Jong Kyong
authors: JK
authors: Kim
authors: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065.
authors: Jonas
authors: J
authors: Marcello
authors: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065.
authors: Terry C
authors: TC
authors: Fang
authors: Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage SG1 2NY, England, UK.
authors: Rab
authors: R
authors: Prinjha
authors: Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
authors: Remy
authors: R
authors: Bosselut
authors: Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065 dobenem@rockefeller.edu tarakho@rockefeller.edu.
authors: Alexander
authors: A
authors: Tarakhovsky
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D002843:Chromatin / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D037182:T-Cell Antigen Receptor Specificity
chemical_list: D015704:CD4 Antigens; D002843:Chromatin; D006657:Histones; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D011948:Receptors, Antigen, T-Cell; C513267:Zbtb16 protein, mouse; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C111778:Utx protein, mouse; C523761:Kdm6b protein, mouse; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D008239:Lysine