Systemic immune activity occurs during human immune system maturation
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<sup>+</sup> T cell subset mediating TOX2<sup>+</sup> precursor cells' transition to mature naive CD4<sup>+</sup> 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<sup>+</sup> 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.
Authors
- Zhao-Hui Ruan
- Hai-Tian Chen
- Dong Ma (ORCID: https://orcid.org/0000-0001-9557-9040)
- Zilian Wang (ORCID: https://orcid.org/0000-0002-8902-8215)
- Tao Luo (ORCID: https://orcid.org/0000-0002-5592-8899)
- Yunhua Tang (ORCID: https://orcid.org/0000-0001-9337-5781)
- Shuai He (ORCID: https://orcid.org/0000-0001-6619-1039)
- Xiaorui Liu (ORCID: https://orcid.org/0000-0002-3273-1268)
- Yujie Gan (ORCID: https://orcid.org/0009-0004-9730-2562)
- Xiao‐Shun He
- Shaofeng Zhang (ORCID: https://orcid.org/0000-0002-9920-2344)
- Jin‐Xin Bei (ORCID: https://orcid.org/0000-0003-1333-407X)
- Chun-Ling Luo
- Wenxin Yan (ORCID: https://orcid.org/0000-0003-2725-9840)
- Tielong Wang (ORCID: https://orcid.org/0000-0001-7547-9819)
- Zihao Xu (ORCID: https://orcid.org/0000-0003-0805-8533)
- Yang Liu (ORCID: https://orcid.org/0000-0002-5221-7725)
- Liang Li (ORCID: https://orcid.org/0000-0002-3997-1360)
- Xiaoyi Wang (ORCID: https://orcid.org/0000-0001-5375-2706)
- Zhiyong Guo (ORCID: https://orcid.org/0000-0002-5458-6268)
- Shunying Zhao (ORCID: https://orcid.org/0000-0002-3011-0433)
- An‐Yi Xu
- Jingjing He (ORCID: https://orcid.org/0000-0003-0322-4846)
- Qitao Huang
- Caixia Zhu
Institutions
- Central South University (CN)
- Sun Yat-sen University (CN)
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- First People's Hospital of Foshan (CN)
- Hunan Cancer Hospital (CN)
- The First Affiliated Hospital, Sun Yat-sen University (CN)
- Boai Hospital of Zhongshan (CN)
- Guangdong Academy of Medical Sciences (CN)
- Sun Yat-sen University Cancer Center (CN)
- Hainan Medical University (CN)
- University of Hong Kong (HK)
- Guangzhou Medical University (CN)
Publication Details
- Journal
- Cell
- Published
- 2025-10-28
- DOI
- https://doi.org/10.1016/j.cell.2025.10.003
- Citations
- 5
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 3.99