{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T04:14:52Z","timestamp":1793333692267,"version":"4.5.0"},"reference-count":99,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100021821","name":"Oncode Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021821","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005040","name":"Bontius Stichting","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005040","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>During 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aim and methodology<\/jats:title>\n                    <jats:p>\n                      To understand the nature and response of maternal CD4\n                      <jats:sup>+<\/jats:sup>\n                      Tregs and CD4\n                      <jats:sup>+<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Data mining revealed novel discerning, as well as shared features and functionalities of decidual CD4\n                      <jats:sup>+<\/jats:sup>\n                      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\n                      <jats:italic>de novo<\/jats:italic>\n                      T-cell priming and dynamic T-cell turnover in the decidua throughout pregnancy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our findings suggest that non-self-reactive CD4\n                      <jats:sup>+<\/jats:sup>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance<\/jats:title>\n                    <jats:p>\n                      These molecular definitions of decidual CD4\n                      <jats:sup>+<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1865340","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T07:15:00Z","timestamp":1785827700000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Defining nature, responses and drivers of regulatory- and conventional CD4+ T cells in the human term decidua"],"prefix":"10.3389","volume":"17","author":[{"given":"Lotte J.","family":"Verleng","sequence":"first","affiliation":[{"name":"Department of Immunology, Leiden University Medical Center","place":["Leiden, Netherlands"]},{"name":"Oncode Institute, Leiden University Medical Center","place":["Leiden, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Busselaar","sequence":"additional","affiliation":[{"name":"Department of Immunology, Leiden University Medical Center","place":["Leiden, Netherlands"]},{"name":"Oncode Institute, Leiden University Medical Center","place":["Leiden, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Mensink","sequence":"additional","affiliation":[{"name":"Department of Immunology, Leiden University Medical Center","place":["Leiden, Netherlands"]},{"name":"Oncode Institute, Leiden University Medical Center","place":["Leiden, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen","family":"Schrama","sequence":"additional","affiliation":[{"name":"Department of Immunology, Leiden University Medical Center","place":["Leiden, Netherlands"]},{"name":"Oncode Institute, Leiden University Medical Center","place":["Leiden, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanneke","family":"Kapsenberg","sequence":"additional","affiliation":[{"name":"Department of Immunology, Leiden University Medical Center","place":["Leiden, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carin","family":"van der Keur","sequence":"additional","affiliation":[{"name":"Department of Immunology, Leiden University Medical Center","place":["Leiden, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Immunology, Leiden University Medical Center","place":["Leiden, Netherlands"]},{"name":"Oncode Institute, Leiden University Medical Center","place":["Leiden, Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Eikmans","sequence":"additional","affiliation":[{"name":"Department of Immunology, Leiden University Medical 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