Systemic immune activity occurs during human immune system maturation
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
Abstract
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.