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

The epigenetic landscape of human alpha beta and gamma delta T cell development has remained unexplored thus far. Taghon and colleagues provide a resource of RNA-seq and ATAC-seq profiles examining human thymocyte development. The development of TCR alpha beta and TCR gamma delta 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 byGATA3- andBCL11B-dependent closing of PU.1 sites. A temporary increase in H3K27me3 without open chromatin modifications is unique for beta-selection, whereas emerging gamma delta T cells, which originate from common precursors of beta-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(+)alpha beta-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