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Sci Transl Med. 2018 Apr 25;10(438). pii: eaan2263. doi: 10.1126/scitranslmed.aan2263.

Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN-γ and TNF-α.

Author information

1
Eli and Edythe Broad Center of Regeneration Medicine, University of California, San Francisco, CA 94143, USA.
2
Department of Surgery, University of California, San Francisco, CA 94143, USA.
3
Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
4
Obstetrics and Gynecology, University of California, San Francisco, CA 94143, USA.
5
Blood Systems Research Institute, San Francisco, CA 94118, USA.
6
Division of Epidemiology, Genetic Epidemiology and Genomics Laboratory, School of Public Health, University of California, Berkeley, CA 94720, USA.
7
Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/National Institutes of Health (NIH)/U.S. Department of Health and Human Services (DHHS), Bethesda, MD 20892, USA.
8
Department of Obstetrics and Gynecology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
9
Department of Microbiology, Immunology, and Biochemistry, Wayne State University School of Medicine, Detroit, MI 48201, USA.
10
Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI 48109, USA.
11
Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI 48824, USA.
12
Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
13
Eli and Edythe Broad Center of Regeneration Medicine, University of California, San Francisco, CA 94143, USA. tippi.mackenzie@ucsf.edu.
14
Center for Maternal-Fetal Precision Medicine, University of California, San Francisco, CA 94143, USA.

Abstract

Healthy pregnancy is the most successful form of graft tolerance, whereas preterm labor (PTL) may represent a breakdown in maternal-fetal tolerance. Although maternal immune responses have been implicated in pregnancy complications, fetal immune responses against maternal antigens are often not considered. To examine the fetal immune system in the relevant clinical setting, we analyzed maternal and cord blood in patients with PTL and healthy term controls. We report here that the cord blood of preterm infants has higher amounts of inflammatory cytokines and a greater activation of dendritic cells. Moreover, preterm cord blood is characterized by the presence of a population of central memory cells with a type 1 T helper phenotype, which is absent in term infants, and an increase in maternal microchimerism. T cells from preterm infants mount a robust proliferative, proinflammatory response to maternal antigens compared to term infants yet fail to respond to third-party antigens. Furthermore, we show that T cells from preterm infants stimulate uterine myometrial contractility through interferon-γ and tumor necrosis factor-α. In parallel, we found that adoptive transfer of activated T cells directly into mouse fetuses resulted in pregnancy loss. Our findings indicate that fetal inflammation and rejection of maternal antigens can contribute to the signaling cascade that promotes uterine contractility and that aberrant fetal immune responses should be considered in the pathogenesis of PTL.

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