Department of Immunology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
Nat Rev Immunol. 2021 Mar;21(3):162-176. doi: 10.1038/s41577-020-00426-6. Epub 2020 Sep 11.
Recent evidence has elucidated how multipotent blood progenitors transform their identities in the thymus and undergo commitment to become T cells. Together with environmental signals, a core group of transcription factors have essential roles in this process by directly activating and repressing specific genes. Many of these transcription factors also function in later T cell development, but control different genes. Here, we review how these transcription factors work to change the activities of specific genomic loci during early intrathymic development to establish T cell lineage identity. We introduce the key regulators and highlight newly emergent insights into the rules that govern their actions. Whole-genome deep sequencing-based analysis has revealed unexpectedly rich relationships between inherited epigenetic states, transcription factor-DNA binding affinity thresholds and influences of given transcription factors on the activities of other factors in the same cells. Together, these mechanisms determine T cell identity and make the lineage choice irreversible.
最近的证据阐明了多能血液祖细胞如何在胸腺中改变其身份,并承诺成为 T 细胞。与环境信号一起,一组核心转录因子通过直接激活和抑制特定基因在这个过程中起着至关重要的作用。许多这些转录因子在以后的 T 细胞发育中也有作用,但控制不同的基因。在这里,我们回顾了这些转录因子如何在早期胸腺内发育过程中改变特定基因组位置的活性,以建立 T 细胞谱系身份。我们介绍了关键的调节剂,并强调了新出现的关于其作用规则的新见解。基于全基因组深度测序的分析揭示了遗传表观遗传状态、转录因子-DNA 结合亲和力阈值以及给定转录因子对同一细胞中其他因子活性的影响之间出乎意料的丰富关系。这些机制共同决定了 T 细胞的身份,并使谱系选择不可逆转。
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