Treg cells retain stable lineage commitment during pregnancy in mice after late gestation inflammatory challenge
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Date
2026
Authors
Foyle, K.L.
Green, E.S.
Walker-Rogers, J.R.
Tran, H.M.
Olson, D.M.
Moldenhauer, L.M.
Robertson, S.A.
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Immunology and Cell Biology, 2026; 103(3):276-311
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Kerrie L Foyle, Ella S Green, Jessie R Walker-Rogers, Ha M Tran, David M Olson, Lachlan M Moldenhauer and Sarah A Robertson
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Abstract
Inflammation is a major driver of preterm birth, a common pregnancy disorder and the leading cause of childhood death. T regulatory (Treg) cells are essential mediators of maternal fetal tolerance and are critical for constraining uterine inflammation. In some tissue settings, loss of Foxp3 expression can cause instability in Treg cell lineage commitment, elevated production of proinflammatory cytokines and compromised suppressive function. Whether preterm birth susceptibility is associated with loss of lineage fidelity and adoption of proinflammatory phenotypes in Treg cells is unknown. In this study, we investigated the lineage stability of Treg cells in vivo in pregnant mice using a Foxp3 fate-mapping system and models of preterm birth induced by late-gestation inflammatory challenge with lipopolysaccharide (LPS) or interleukin-1β (IL-1β). Ex-Foxp3-expressing (ex-Foxp3) cells were observed in the uterus-draining lymph nodes (udLNs) in non-pregnant mice and in similar abundance across normal gestation, and a proportion expressed proinflammatory cytokines IFNγ and/or IL-17A. Bulk RNA-sequencing of sorted Treg and ex-Foxp3 cells from late-gestation udLNs revealed substantial loss of the Treg cell lineage program in ex-Foxp3 cells, characterized by reversal in expression of canonical Treg cell genes and pathways. Late gestation LPS or IL-1β administration to induce preterm birth did not expand the ex-Foxp3 cell population in the uDLNs or uterine decidua. We conclude that uterine Treg cells exhibit a high level of lineage stability in pregnancy regardless of proinflammatory challenge. Whether there is any biological or pathophysiological significance of ex-Foxp3 cells in gestational tissues remains to be defined.
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© 2026 The Author(s). Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.