Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY, USA.
EMBO J. 2020 Jul 1;39(13):e104159. doi: 10.15252/embj.2019104159. Epub 2020 Jun 8.
γδ T cells with distinct properties develop in the embryonic and adult thymus and have been identified as critical players in a broad range of infections, antitumor surveillance, autoimmune diseases, and tissue homeostasis. Despite their potential value for immunotherapy, differentiation of γδ T cells in the thymus is incompletely understood. Here, we establish a high-resolution map of γδ T-cell differentiation from the fetal and adult thymus using single-cell RNA sequencing. We reveal novel sub-types of immature and mature γδ T cells and identify an unpolarized thymic population which is expanded in the blood and lymph nodes. Our detailed comparative analysis reveals remarkable similarities between the gene networks active during fetal and adult γδ T-cell differentiation. By performing a combined single-cell analysis of Sox13, Maf, and Rorc knockout mice, we demonstrate sequential activation of these factors during IL-17-producing γδ T-cell (γδT17) differentiation. These findings substantially expand our understanding of γδ T-cell ontogeny in fetal and adult life. Our experimental and computational strategy provides a blueprint for comparing immune cell differentiation across developmental stages.
γδ T 细胞具有独特的特性，它们在胚胎期和成人胸腺中发育，并被认为是广泛的感染、抗肿瘤监视、自身免疫性疾病和组织稳态的关键参与者。尽管它们在免疫治疗中有潜在的价值，但胸腺中 γδ T 细胞的分化还不完全清楚。在这里，我们使用单细胞 RNA 测序建立了一个从胎儿和成人胸腺中 γδ T 细胞分化的高分辨率图谱。我们揭示了新型的未成熟和成熟 γδ T 细胞亚群，并鉴定了一个在血液和淋巴结中扩增的未极化胸腺群体。我们详细的比较分析揭示了胎儿和成人 γδ T 细胞分化过程中活性基因网络之间的惊人相似性。通过对 Sox13、Maf 和 Rorc 敲除小鼠进行单细胞分析的组合分析，我们证明了这些因子在产生 IL-17 的 γδ T 细胞 (γδT17) 分化过程中的顺序激活。这些发现大大扩展了我们对胎儿和成人生活中 γδ T 细胞发生的理解。我们的实验和计算策略为比较不同发育阶段的免疫细胞分化提供了蓝图。
