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.

TCRαβ和TCRγδT细胞的发育包括逐步过程，其中调节事件控制分化和谱系结果。为了阐明这些机制，我们对代表人类T细胞发育连续性的明确定义的胸腺细胞亚群采用RNA测序，ATAC测序和ChIPmentation。染色质可及性动力学显示明确的阶段特异性，并揭示人类T细胞谱系承诺以GATA3-和BCL11B为标志依赖的PU.1网站关闭。H3K27me3的临时增加而没有开放的染色质修饰对于β选择是独特的，而新兴的γδT细胞起源于β选择细胞的常见前体，由于强的T细胞受体（TCR）信号传导，显示出大量的染色质可及性变化。此外，我们揭示了支持其效应子功能的CD4 ⁺和CD8 ⁺ αβ谱系细胞之间不同的染色质分布，揭示了定义成熟T细胞的基因特异性机制。该资源提供了一个框架，用于研究驱动正常和恶性人类T细胞发育的基因调控机制。