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An imbalance between innate and adaptive immune cells at the maternal–fetal interface occurs prior to endotoxin-induced preterm birth

Cellular & Molecular Immunology volume 13, pages 462–473 (2016)Cite this article

Abstract

Preterm birth (PTB) is the leading cause of neonatal morbidity and mortality worldwide. A transition from an anti-inflammatory state to a pro-inflammatory state in the mother and at the maternal–fetal interface has been implicated in the pathophysiology of microbial-induced preterm labor. However, it is unclear which immune cells mediate this transition. We hypothesized that an imbalance between innate and adaptive immune cells at the maternal–fetal interface will occur prior to microbial-induced preterm labor. Using an established murine model of endotoxin-induced PTB, our results demonstrate that prior to delivery there is a reduction of CD4+ regulatory T cells (Tregs) in the uterine tissues. This reduction is neither linked to a diminished number of Tregs in the spleen, nor to an impaired production of IL10, CCL17, or CCL22 by the uterine tissues. Endotoxin administration to pregnant mice does not alter effector CD4+ T cells at the maternal–fetal interface. However, it causes an imbalance between Tregs (CD4+ and CD8+), effector CD8+ T cells, and Th17 cells in the spleen. In addition, endotoxin administration to pregnant mice leads to an excessive production of CCL2, CCL3, CCL17, and CCL22 by the uterine tissues as well as abundant neutrophils. This imbalance in the uterine microenvironment is accompanied by scarce APC-like cells such as macrophages and MHC II+ neutrophils. Collectively, these results demonstrate that endotoxin administration to pregnant mice causes an imbalance between innate and adaptive immune cells at the maternal–fetal interface.

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Acknowledgements

This research was supported by the Wayne State University Perinatal Research Initiative in Maternal, Perinatal and Child Health, and by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS). We gratefully acknowledge Marcus Lehr, Dr Zhong Dong, Lorri McLuckie, and Rona Wang for their contributions to the execution of this study, and to Maureen McGerty and Amy E. Furcron (Wayne State University) for their critical readings of the manuscript.

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Authors and Affiliations

  1. Department of Obstetrics & Gynecology, Wayne State University School of Medicine, Detroit, Michigan, USA

    Marcia Arenas-Hernandez, Derek St Louis, Sonia S Hassan, Emily B Kaye & Nardhy Gomez-Lopez

  2. Division of Intramural Research, Perinatology Research Branch, Program for Perinatal Research and Obstetrics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NICHD/NIH/DHHS, Bethesda, Detroit, Maryland, Michigan, USA

    Marcia Arenas-Hernandez, Roberto Romero, Derek St Louis, Sonia S Hassan & Nardhy Gomez-Lopez

  3. Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan, USA

    Roberto Romero

  4. Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, Michigan, USA

    Roberto Romero

  5. Department of Molecular Obstetrics and Genetics, Wayne State University, Detroit, Michigan, USA

    Roberto Romero

  6. Department of Immunology & Microbiology, Wayne State University School of Medicine, Detroit, Michigan, USA

    Nardhy Gomez-Lopez

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  1. Marcia Arenas-Hernandez
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Arenas-Hernandez, M., Romero, R., St Louis, D. et al. An imbalance between innate and adaptive immune cells at the maternal–fetal interface occurs prior to endotoxin-induced preterm birth. Cell Mol Immunol 13, 462–473 (2016). https://doi.org/10.1038/cmi.2015.22

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