BRIEF RESEARCH REPORT article
Front. Immunol.
Sec. Immunological Tolerance and Regulation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1634430
Hyporesponsive fetus-specific T cell responses in multiparous human pregnancy
Provisionally accepted
- The University of Chicago, Chicago, United States
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Pregnancy acts as both a tolerogenic and sensitizing event, inducing T cell hypofunction and humoral sensitization. Mouse studies have reported that T cell hypofunction is a key mechanism in preserving fetal viability, but this phenomenon remains uncharacterized in humans. In this study, we developed an assay to assess fetal-specific T cell tolerance in uncomplicated, full-term human pregnancies. The majority of maternal PBMCs stimulated with matured fetus-matched dendritic cells (CBDCs) exhibited low IFNγ responses that were significantly lower than third-party fetus-unmatched CBDCs. This hyporesponsiveness to matched CBDCs extended to the production of a range of Th1 and Th2 cytokines, and was not associated with increased immunoregulatory cytokines, IL-10 or IL-1RA. A small number of grand multiparous individuals displayed heightened IFNγ responses to fetus-matched CBDCs; these individuals also exhibited heightened Th1 and Th2 cytokine responses. Together, our study introduces a novel assay to measure fetal antigen-specific T cell responses, and T cell hypofunction as an immunological mechanism enabling successful pregnancy in humans and mouse. It also implicates alternative tolerance mechanisms that allow successful pregnancies to proceed even in the presence of fetus-specific T effector cell reactivity. This study has implications for understanding immune dysregulation in pregnancy complications and for improving transplantation outcomes for multiparous women.
Keywords: Maternal-fetal tolerance, T cell tolerance, Multiparous pregnancy, Pregnancy, ELISpot assay, fetus-specific responses
Received: 24 May 2025; Accepted: 04 Jul 2025.
Copyright: © 2025 Morgan, Hynes, Pollard, Andrade, Cheol and Chong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Anita S Chong, The University of Chicago, Chicago, United States
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