Frontiers in Immunology · Published 2026-08-04 · DOI 10.3389/fimmu.2026.1865340
Lotte J. Verleng, Julia Busselaar, Mark Mensink, Ellen Schrama, Hanneke Kapsenberg, Carin van der Keur, Xin Lei, Michael Eikmans, Yanling Xiao, Sander de Kivit, Jannie Borst
BackgroundDuring mammalian pregnancy, a maternal immunoregulatory network develops in the decidua that fosters fetal development, maintains tolerance to fetal antigens and protects against infection. Herein, decidual regulatory T cells (Tregs) are crucial for pregnancy success.Aim and methodologyTo understand the nature and response of maternal CD4+ Tregs and CD4+ conventional T-cells (Tconv) in healthy human pregnancy, we analyzed these cells in decidua and blood at term, caesarean delivery by single-cell transcriptomics and TCR sequencing.ResultsData mining revealed novel discerning, as well as shared features and functionalities of decidual CD4+ Tregs and Tconvs. Both cell types showed evidence of antigen recognition and activation in the decidua, followed by local clonal expansion and effector differentiation. Tregs were largely of the thymus-derived (t)Treg lineage that has a self-antigen reactive T cell receptor (TCR) repertoire. Tregs locally expanded, more so than Tconvs, and differentiated into typical non-lymphoid tissue (NLT)-resident effector cells with discerning cell surface markers and multiple suppressive functions, driven by TNF receptor-2 costimulation. Additional factors, including IFNs, interleukins and prolactin emerged as shared drivers of decidual Treg and Tconv effector differentiation. Effector Tconvs had cell lineage-discerning proinflammatory and cytotoxic capacities, restrained by cell-intrinsic and -extrinsic mechanisms, while sharing glycolytic and antigen-presenting features with Tregs. Treg and Tconv subpopulations showed signs of exhaustion, suggesting chronic antigenic stimulation. Overall, the observed features argue for ongoing de novo T-cell priming and dynamic T-cell turnover in the decidua throughout pregnancy.ConclusionOur findings suggest that non-self-reactive CD4+ Tconvs and self-reactive tTregs are continuously primed in lymphoid organs during pregnancy, reactivated by antigen in the decidua and dynamically turned over. In the decidua, CD4+ Tconvs and Tregs expand and differentiate under influence of specific cytokines into tissue-resident effector cells with opposing and restrained pro- and anti-inflammatory functions, as well as shared antigen-presenting capacity.SignificanceThese molecular definitions of decidual CD4+ Tregs and Tconvs can be used to aid diagnostics at mRNA and protein level. Moreover, they facilitate mechanistic understanding of maternal-fetal tolerance, based on extrapolation of known T-cell lineage characteristics and tissue adaptations in health and disease.
Abstract from DOAJ. Public domain (CC0 1.0).
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Verleng, L., Busselaar, J., Mensink, M., et al. (2026). Defining nature, responses and drivers of regulatory- and conventional CD4+ T cells in the human term decidua. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2026.1865340