Systemic immune activity occurs during human immune system maturation

作者：Shuai He, Chun-Ling Luo, Tao Luo, Hai-Tian Chen, Shaofeng Zhang, Jia-Xin Jiang, Xiaoyi Wang, Dong Ma, Shuang-Lian Zhao, An‐Yi Xu, Jingjing He, Zhao-Hui Ruan, Wenxin Yan, Zihao Xu, Yang Liu, Qitao Huang, Yujie Gan, Tielong Wang, Yunhua Tang, Xiaorui Liu, Caixia Zhu, Liang Li, Zilian Wang, Zhiyong Guo, Jin‐Xin Bei, Xiao‐Shun He · 发表于：Cell · 年份：2025 · DOI：10.1016/j.cell.2025.10.003 · 被引用次数：9 · 研究领域：T-cell and B-cell Immunology、Immunotoxicology and immune responses、Artificial Immune Systems Applications

The second trimester of pregnancy is a pivotal stage in human immune system development. Utilizing single-cell RNA sequencing and T cell receptor sequencing, we profiled 2,868,420 immune cells from 321 samples across 23 organs, including adult tissues as comparators. We identify an extrathymic CD4 + T cell subset mediating TOX2 + precursor cells' transition to mature naive CD4 + T cells. Contrary to the prevailing paradigm of fetal immune quiescence, we uncover widespread memory/activated T cells and tissue-resident memory clones shared across organs, indicating systemic immune activity beyond localized barrier defense. Cell-cell communication and functional assays indicate two tolerance mechanisms that suppress fetal T cell activation: ARG1 + neutrophils and a PTGES3/PTGER4 signaling pathway. We also find that hematopoietic stem cells (HSCs) disperse across multiple organs and show that HSCs from non-canonical hematopoietic organs differentiate into diverse immune lineages. These findings provide insights into human immune system maturation and tolerance in fetuses and adults.