Pregnancy-acquired memory CD4+ regulatory T cells improve pregnancy outcome in mice

Kristin Thiele (), Christopher Urbschat, Julia. Isabel. Amambay Riquelme, Lisa. Sophie Ahrendt, Ronja Wöhrle, Steven Schepanski, Judith Joana Eckert, Etienne Becht, Minyue Qi, Malik Alawi, Martin Becker, Nicola Gagliani, Hans-Willi Mittrücker, Anke Diemert and Petra Clara Arck ()
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Kristin Thiele: University Medical Center Hamburg-Eppendorf
Christopher Urbschat: University Medical Center Hamburg-Eppendorf
Julia. Isabel. Amambay Riquelme: University Medical Center Hamburg-Eppendorf
Lisa. Sophie Ahrendt: University Medical Center Hamburg-Eppendorf
Ronja Wöhrle: University Medical Center Hamburg-Eppendorf
Steven Schepanski: University Medical Center Hamburg-Eppendorf
Judith Joana Eckert: University Medical Center Hamburg-Eppendorf
Etienne Becht: Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center
Minyue Qi: University Medical Center Hamburg-Eppendorf
Malik Alawi: University Medical Center Hamburg-Eppendorf
Martin Becker: University of Rostock
Nicola Gagliani: University Medical Center Hamburg-Eppendorf
Hans-Willi Mittrücker: University Medical Center Hamburg-Eppendorf
Anke Diemert: University Medical Centre Hamburg-Eppendorf
Petra Clara Arck: University Medical Center Hamburg-Eppendorf

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Subsequent pregnancies are generally less prone to obstetric complications. A successful pregnancy outcome requires pivotal immunological adaptation to ensure immune tolerance towards the foetus. Thus, the lower risk for pregnancy complication during subsequent pregnancies may be attributable to immune memory mounted during first pregnancies. Here we identify higher frequencies of fetal-antigen-specific CD4+ regulatory T (Treg) cells both postpartum and in subsequent pregnancies in mice which are partly originating from trans-differentiated Th17 cells. Our functional experiments demonstrate that these CD4+ Treg cells have memory functions (CD4+ mTreg) and account for an improved fetal development and pregnancy outcome, also during adverse conditions, such as gestational sound stress. Using a high-throughput single-cell quantification method, we identify candidate markers for the detection of CD4+ mTreg cells, which include CXCR4 and CD274. Our findings thus contribute to the improved understanding of pregnancy-induced immune memory and foster the identification of immune targets aiming to reduce the risk for immune-mediated pregnancy complications.

Date: 2025
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DOI: 10.1038/s41467-025-61572-w

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