A disrupted FOXP3 transcriptional signature underpins systemic regulatory T cell insufficiency in early pregnancy failure

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dc.contributor.authorMoldenhauer, L.M.
dc.contributor.authorFoyle, K.L.
dc.contributor.authorWilson, J.J.
dc.contributor.authorWong, Y.Y.
dc.contributor.authorSharkey, D.J.
dc.contributor.authorGreen, E.S.
dc.contributor.authorBarry, S.C.
dc.contributor.authorHull, M.L.
dc.contributor.authorRobertson, S.A.
dc.date.issued2024
dc.description.abstractRegulatory T (Treg) cell defects are implicated in disorders of embryo implantation and placental development, but the origins of Treg cell dysfunction are unknown. Here, we comprehensively analyzed the phenotypes and transcriptional profile of peripheral blood Treg cells in individuals with early pregnancy failure (EPF). Compared to fertile subjects, EPF subjects had 32% fewer total Treg cells and 54% fewer CD45RA+CCR7+ naive Treg cells among CD4+ T cells, an altered Treg cell phenotype with reduced transcription factor FOXP3 and suppressive marker CTLA4 expression, and lower Treg:Th1 and Treg:Th17 ratios. RNA sequencing demonstrated an aberrant gene expression profile, with upregulation of pro-inflammatory genes including CSF2, IL4, IL17A, IL21, and IFNG in EPF Treg cells. In silico analysis revealed 25% of the Treg cell dysregulated genes are targets of FOXP3. We conclude that EPF is associated with systemic Treg cell defects arising due to disrupted FOXP3 transcriptional control and loss of lineage fidelity.
dc.description.statementofresponsibilityLachlan M. Moldenhauer, Kerrie L. Foyle, Jasmine J. Wilson, Ying Y. Wong, David J. Sharkey, Ella S. Green, Simon C. Barry, M. Louise Hull, Sarah A. Robertson
dc.identifier.citationiScience, 2024; 27(2):108994-1-108994-23
dc.identifier.doi10.1016/j.isci.2024.108994
dc.identifier.issn2589-0042
dc.identifier.issn2589-0042
dc.identifier.orcidMoldenhauer, L.M. [0000-0002-3141-2521]
dc.identifier.orcidFoyle, K.L. [0000-0002-2663-4621]
dc.identifier.orcidWong, Y.Y. [0000-0002-3472-5080]
dc.identifier.orcidSharkey, D.J. [0000-0002-4831-7950]
dc.identifier.orcidGreen, E.S. [0000-0002-3009-3442]
dc.identifier.orcidBarry, S.C. [0000-0002-0597-7609]
dc.identifier.orcidHull, M.L. [0000-0003-1813-3971] [0000-0003-4660-4005]
dc.identifier.orcidRobertson, S.A. [0000-0002-9967-0084]
dc.identifier.urihttps://hdl.handle.net/2440/140619
dc.language.isoen
dc.publisherElsevier BV
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1041332
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1139509
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT9000112
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/GNT1038556
dc.relation.granthttp://purl.org/au-research/grants/arc/LE0668241
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1063808
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1099461
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1120543
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1120989
dc.rights© 2024 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.source.urihttp://dx.doi.org/10.1016/j.isci.2024.108994
dc.subjectRegulatory T (Treg) cell defects
dc.titleA disrupted FOXP3 transcriptional signature underpins systemic regulatory T cell insufficiency in early pregnancy failure
dc.typeJournal article
pubs.publication-statusPublished

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