Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation.

Autor:	Dobenecker MW; Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065 dobenem@rockefeller.edu tarakho@rockefeller.edu., Kim JK; Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892., Marcello J; Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065., Fang TC; Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065., Prinjha R; Epinova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline R&D, Medicines Research Centre, Stevenage SG1 2NY, England, UK., Bosselut R; Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892., Tarakhovsky A; Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, NY 10065 dobenem@rockefeller.edu tarakho@rockefeller.edu.
Jazyk:	angličtina
Zdroj:	The Journal of experimental medicine [J Exp Med] 2015 Mar 09; Vol. 212 (3), pp. 297-306. Date of Electronic Publication: 2015 Feb 16.
DOI:	10.1084/jem.20141499
Abstrakt:	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. (© 2015 Dobenecker et al.)
Databáze:	MEDLINE
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