Epigenetic instability and hypofunctionality of fetal Tregs allow a permissive regulatory environment for T effector memory maturation

The human gestational environment is commonly perceived to be predominantly suppressive and incompatible for T effector maturation. However, evidence of a competent effector fetal environment is mounting in the field. Here, we employed a high parametric, mass cytometry-based approach to study the fetal circulatory and microenvironmental immunomes, with the aim to understand the inception and extent of fetal effector T cell priming and its relation with regulatory mechanisms. We found evidence of fetal thymic immune imprinting, coupled with both circulatory and tissue effector memory development. Correspondingly, in the regulatory compartment, we detected the presence of Tbet<sup>+</sup>Treg in fetal tissues at elevated levels compared to adult tissues. Fetal Tregs, though capable of suppression, were hyposuppressive as compared with adult counterparts. We found that a proportion of fetal Tregs lost FoxP3 commitment during proliferation and exhibited higher TCR clonotype sharing with effector T cells, indicating higher plasticity in fetal Tregs than adult. Epigenetic profiling of the FoxP3 promoter locus reveals that fetal Tregs were only partially demethylated, possibly explaining the observed instability. In summary, our data provide evidence of a regulatory environment in the 2nd trimester permissive for T effector maturation, in part contributed by the relative instability and hypofunctionality in fetal Tregs.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2025-07-24
DOI
https://doi.org/10.1073/pnas.2506673122
Citations
1
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
0.80

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article

Epigenetic instability and hypofunctionality of fetal Tregs allow a permissive regulatory environment for T effector memory maturation

Shi Huan Tay, Xiahui Tan, Maria V. Papadopoulou, Su Li Poh et al.
1 citations
Proceedings of the National Academy of Sciences
Immune Cell Function and Interaction
0.80
article

Epigenetic instability and hypofunctionality of fetal Tregs allow a permissive regulatory environment for T effector memory maturation

Shi Huan Tay, Xiahui Tan, Maria V. Papadopoulou, Su Li Poh, Charles‐Antoine Dutertre, C Donner, Naomi McGovern, Sharifah Nur Hazirah, Lakshmi Ramakrishna, Thaschawee Arkachaisri, Camillus Chua, Pavanish Kumar, David Vermijlen, Fauziah Ally, Florent Ginhoux, Joo Guan Yeo, Archita Mishra, Salvatore Albani, Phyllis Chen, Martin Wasser, Jing Yao Leong, Nursyuhadah Sutamam, Liang Xie, Yiping Fan, Feyza Nur Azman, Jerry Kok Yen Chan
article en
1 citations

Abstract

The human gestational environment is commonly perceived to be predominantly suppressive and incompatible for T effector maturation. However, evidence of a competent effector fetal environment is mounting in the field. Here, we employed a high parametric, mass cytometry-based approach to study the fetal circulatory and microenvironmental immunomes, with the aim to understand the inception and extent of fetal effector T cell priming and its relation with regulatory mechanisms. We found evidence of fetal thymic immune imprinting, coupled with both circulatory and tissue effector memory development. Correspondingly, in the regulatory compartment, we detected the presence of Tbet<sup>+</sup>Treg in fetal tissues at elevated levels compared to adult tissues. Fetal Tregs, though capable of suppression, were hyposuppressive as compared with adult counterparts. We found that a proportion of fetal Tregs lost FoxP3 commitment during proliferation and exhibited higher TCR clonotype sharing with effector T cells, indicating higher plasticity in fetal Tregs than adult. Epigenetic profiling of the FoxP3 promoter locus reveals that fetal Tregs were only partially demethylated, possibly explaining the observed instability. In summary, our data provide evidence of a regulatory environment in the 2nd trimester permissive for T effector maturation, in part contributed by the relative instability and hypofunctionality in fetal Tregs.

Proceedings of the National Academy of SciencesVol. 122(30)
Agency for Science, Technology and Research (SG), The University of Sydney (AU), Université Libre de Bruxelles (BE), SingHealth (SG), National University of Singapore (SG), La Trobe University (AU), University of Cambridge (GB), Singapore Immunology Network (SG), Institut Gustave Roussy (FR), La Ligue Contre le Cancer (FR), SingHealth Duke-NUS Academic Medical Centre (SG), KK Women's and Children's Hospital (SG), Walloon Excellence in Lifesciences and Biotechnology (BE)
Wellcome Trust, Duke-NUS Medical School, Human Frontier Science Program, National Research Foundation, Agency for Science, Technology and Research, National University of Singapore, National Research Foundation Singapore, Institut National de la Santé et de la Recherche Médicale, University of Sydney, Fonds De La Recherche Scientifique - FNRS, Institut Gustave-Roussy, Walloon excellence in life sciences and biotechnology, Medical Research Council, National Medical Research Council, Biomedical Research Council
Openalex Percentile: Top 26%
Immune Cell Function and Interaction
0.80
DOIOpen Access PDFOpenAlex
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