Systemic immune activity occurs during human immune system maturation

  • Cell. 2025 Dec 11;188(25):7291-7308.e23. doi: 10.1016/j.cell.2025.10.003.
Shuai He  1 ,  Chun-Ling Luo  2 ,  Tao Luo  1 ,  Hai-Tian Chen  3 ,  Shao-Feng Zhang  3 ,  Jia-Xin Jiang  2 ,  Xiao-Yi Wang  4 ,  Dong Ma  5 ,  Shuang-Lian Zhao  4 ,  An-Yi Xu  2 ,  Jing-Jing He  6 ,  Zhao-Hui Ruan  7 ,  Wen-Xin Yan  2 ,  Zi-Hao Xu  2 ,  Yang Liu  2 ,  Qi-Tao Huang  8 ,  Yu-Jie Gan  9 ,  Tie-Long Wang  1 ,  Yun-Hua Tang  1 ,  Xiao-Rui Liu  1 ,  Cai-Xia Zhu  3 ,  Liang Li  10 ,  Zi-Lian Wang  11 ,  Zhi-Yong Guo  12 ,  Jin-Xin Bei  13 ,  Xiao-Shun He  14
Affiliations
  • 1. State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China.
  • 2. State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China.
  • 3. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou 510080, P.R. China.
  • 4. Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, P.R. China.
  • 5. Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, P.R. China.
  • 6. Hainan Academy of Medical Sciences, Hainan Medical University, Haikou 571199, P.R. China.
  • 7. Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, P.R. China.
  • 8. Department of Obstetrics and Gynecology, The First People's Hospital of Foshan, Foshan 528000, P.R. China.
  • 9. Prenatal Diagnosis Center, Boai Hospital of Zhongshan, Zhongshan 528400, P.R. China.
  • 10. Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, P.R. China.
  • 11. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-Sen University, Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou 510080, P.R. China. Electronic address: [email protected].
  • 12. State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China; NHC Key Laboratory of Assisted Circulation, Sun Yat-sen University, Guangzhou 510080, P.R. China. Electronic address: [email protected].
  • 13. State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China; Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing 211103, P.R. China; Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, 169610 Singapore; Sun Yat-sen University Institute of Advanced Studies Hong Kong, Science Park, Hong Kong SAR, P.R. China; Department of Medical Oncology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, P.R. China. Electronic address: [email protected].
  • 14. State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China; Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China; Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, P.R. China. Electronic address: [email protected].
PMID: 41161316 DOI: 10.1016/j.cell.2025.10.003
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.

Keywords
ARG1; PTGES3–PTGER4; T cell receptor; fetal immunity; hematopoietic stem cell; neutrophil; second trimester; single-cell RNA sequencing; tissue-resident memory T cell.
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