Epigenetic instability and hypofunctionality of fetal Tregs allow a permissive regulatory environment for T effector memory maturation
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 + 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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (26)
Jing Yao Leong
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Naomi McGovern
Centre for Trophoblast Research, Department of Pathology, University of Cambridge
Archita Mishra
Singapore Immunology Network, Agency for Science, Technology and Research
Martin Wasser
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Pavanish Kumar
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Shi Huan Tay
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Sharifah Nur Hazirah
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Joo Guan Yeo
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Xiu Qi Tan
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Nursyuhadah Sutamam
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Farah Nadiah Azman
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Camillus Jian Hui Chua
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Phyllis ZiXuan Chen
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Fauziah Ally
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Charles-Antoine Dutertre
Gustave Roussy Cancer Campus
Lakshmi Ramakrishna
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Su Li Poh
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Liang Xie
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Yiping Fan
Department of Reproductive Medicine, KK Women’s and Children’s Hospital
Catherine Donner
Department of Obstetrics and Gynecology, Hôpital Erasme, Université Libre de Bruxelles
Maria Papadopoulou
Department of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles
David Vermijlen
Department of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles
Thaschawee Arkachaisri
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia
Jerry Kok Yen Chan
Florent Ginhoux
Salvatore Albani
Translational Immunology Institute, Singhealth/Duke-National University of Singapore, Academic Medical Centre, The Academia