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The initiation of cell-mediated immunity can be observed as early as the third month of fetal growth, with active antibody-mediated immunity following approximately one month later.
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The T and B lymphocytes of the adaptive immune system develop from common lymphoid progenitor cells in the bone marrow. These progenitors give rise to precursors that eventually develop into both T and B lymphocytes. As these precursors mature, they gain the ability to detect and respond to foreign antigens in the body, a process known as immunocompetence. Additionally, these precursors acquire self-tolerance, a process that ensures they do not react to self-antigens. This intricate system...
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The adaptive immune response, a sophisticated defense mechanism, relies on the activation and differentiation of B lymphocytes, or B cells. These processes enable our bodies to mount a tailored response against specific pathogens such as bacteria, free virus particles, toxins, and parasites.
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Systemic immune activity occurs during human immune system maturation.

Shuai He1, Chun-Ling Luo2, Tao Luo1

  • 1State 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.

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|October 29, 2025
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Summary

During pregnancy, fetal immune cells are active and widespread, challenging previous beliefs of immune dormancy. Researchers discovered novel tolerance mechanisms and immune cell development pathways in fetuses.

Keywords:
ARG1PTGES3–PTGER4T cell receptorfetal immunityhematopoietic stem cellneutrophilsecond trimestersingle-cell RNA sequencingtissue-resident memory T cell

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Area of Science:

  • Immunology
  • Developmental Biology
  • Genomics

Background:

  • The second trimester is critical for human immune system development.
  • Previous understanding suggested fetal immune quiescence, with limited systemic activity.
  • The role of extrathymic T cell development and immune tolerance in fetuses requires further elucidation.

Purpose of the Study:

  • To comprehensively profile immune cell populations and their development during the second trimester of human pregnancy.
  • To investigate the mechanisms of immune tolerance in the fetal environment.
  • To explore the distribution and differentiation potential of hematopoietic stem cells (HSCs) in fetuses.

Main Methods:

  • Single-cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing were employed.
  • Analysis of 2,868,420 immune cells from 321 samples across 23 fetal and adult organs.
  • Cell-cell communication analysis and functional assays were conducted.

Main Results:

  • Identification of an extrathymic CD4+ T cell subset involved in naive T cell maturation.
  • Discovery of widespread fetal memory/activated T cells and shared tissue-resident memory clones across organs, indicating systemic immune activity.
  • Uncovered two fetal immune tolerance mechanisms: ARG1+ neutrophils and a PTGES3/PTGER4 signaling pathway.
  • Observed dispersal and differentiation of hematopoietic stem cells (HSCs) from various organs.

Conclusions:

  • The fetal immune system exhibits significant systemic activity and complexity, contrary to quiescence paradigms.
  • Novel pathways for T cell development and immune tolerance in fetuses have been identified.
  • Hematopoietic stem cells show broad distribution and differentiation potential in fetal development, impacting immune lineage diversity.