Distinct and temporary-restricted epigenetic mechanisms regulate human αβ and γδ T cell development

• Published in: Nature immunology Vol. 21; no. 10; pp. 1280 - 1292
• Main Authors: Roels, Juliette, Kuchmiy, Anna, De Decker, Matthias, Strubbe, Steven, Lavaert, Marieke, Liang, Kai Ling, Leclercq, Georges, Vandekerckhove, Bart, Van Nieuwerburgh, Filip, Van Vlierberghe, Pieter, Taghon, Tom
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2020; Nature Publishing Group
• Subjects: 631/250/1619/554/1775; 631/250/1619/554/2509; 631/250/232/2058; 631/250/2502/2170; Biomedical and Life Sciences; Biomedicine; CD4 antigen; CD8 antigen; Cell Differentiation; Cell Lineage; Cells, Cultured; Chromatin; Chromatin - metabolism; Clonal Selection, Antigen-Mediated; Effector cells; Epigenesis, Genetic; Epigenetics; GATA-3 protein; GATA3 Transcription Factor - genetics; GATA3 Transcription Factor - metabolism; Gene Expression Regulation, Neoplastic; Histones - metabolism; Humans; Immunology; Infectious Diseases; Lymphocyte Activation; Lymphocytes; Lymphocytes T; PU.1 protein; Receptors, Antigen, T-Cell, alpha-beta - metabolism; Receptors, Antigen, T-Cell, gamma-delta - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Resource; Ribonucleic acid; RNA; Sequence Analysis, RNA; Signal Transduction; T cell receptors; T-Lymphocytes - physiology; Thymocytes - physiology; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 1529-2908; 1529-2916
• DOI: 10.1038/s41590-020-0747-9

The development of TCRαβ and TCRγδ T cells comprises a step-wise process in which regulatory events control differentiation and lineage outcome. To clarify these mechanisms, we employed RNA-sequencing, ATAC–sequencing and ChIPmentation on well-defined thymocyte subsets that represent the continuum of human T cell development. The chromatin accessibility dynamics show clear stage specificity and reveal that human T cell-lineage commitment is marked by GATA3 - and BCL11B -dependent closing of PU.1 sites. A temporary increase in H3K27me3 without open chromatin modifications is unique for β-selection, whereas emerging γδ T cells, which originate from common precursors of β-selected cells, show large chromatin accessibility changes due to strong T cell receptor (TCR) signaling. Furthermore, we unravel distinct chromatin landscapes between CD4 + and CD8 + αβ-lineage cells that support their effector functions and reveal gene-specific mechanisms that define mature T cells. This resource provides a framework for studying gene regulatory mechanisms that drive normal and malignant human T cell development. The epigenetic landscape of human αβ and γδT cell development has remained unexplored thus far. Taghon and colleagues provide a resource of RNA-seq and ATAC–seq profiles examining human thymocyte development.