Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development
Distinct Notch1 and BCL11B requirements mediate human γδ/αβ T cell development
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DOI：
10.15252/embr.201949006
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发表时间：
2020-04-07
期刊：
影响因子：
7.7
通讯作者：
Taghon, Tom
中科院分区：
文献类型：
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作者：
Dolens, Anne-Catherine;Durinck, Kaat;Taghon, Tom
γ-δ和α-β T细胞在免疫中具有独特的作用，并且两者都通过不同但不清楚的机制起源于胸腺中的T-谱系定向前体。在这里，我们表明，Notch 1激活是更严格地要求人类γ δ发展相比，α β谱系分化，并进行配对的mRNA和miRNA分析跨越11个离散的发展阶段的人类T细胞的发展，以确定潜在的Notch 1下游机制。我们的数据表明，miR-17-92簇是未成熟胸腺细胞中的Notch 1靶点，并且miR-17可以限制这些Notch依赖性T细胞前体中的BCL 11 B表达。我们表明，强制miR-17表达促进人γ δ T细胞的发育，并且一致地，BCL 11B是α β绝对必需的，但γ δ T细胞发育较少。这项研究表明，人类γ δ T细胞的发育是由阶段特异性Notch驱动的负反馈环介导的，通过该负反馈环，miR-17暂时限制BCL 11B的表达，并提供了对人类背景下疾病相关基因BCL 11B和miR-17-92簇的发育作用的功能性见解。
gamma delta and alpha beta T cells have unique roles in immunity and both originate in the thymus from T-lineage committed precursors through distinct but unclear mechanisms. Here, we show that Notch1 activation is more stringently required for human gamma delta development compared to alpha beta-lineage differentiation and performed paired mRNA and miRNA profiling across 11 discrete developmental stages of human T cell development in an effort to identify the potential Notch1 downstream mechanism. Our data suggest that the miR-17-92 cluster is a Notch1 target in immature thymocytes and that miR-17 can restrict BCL11B expression in these Notch-dependent T cell precursors. We show that enforced miR-17 expression promotes human gamma delta T cell development and, consistently, that BCL11B is absolutely required for alpha beta but less for gamma delta T cell development. This study suggests that human gamma delta T cell development is mediated by a stage-specific Notch-driven negative feedback loop through which miR-17 temporally restricts BCL11B expression and provides functional insights into the developmental role of the disease-associated genes BCL11B and the miR-17-92 cluster in a human context.