Exhausted and Senescent T Cells at the Maternal-Fetal Interface in Preterm and Term Labor

Abstract

Successful pregnancy requires a tightly-regulated equilibrium of immune cell interactions at the maternal-fetal interface (i.e., the decidual tissues), which plays a central role in the inflammatory process of labor. Most of the innate immune cells in this compartment have been well characterized; however, adaptive immune cells are still under investigation. Herein, we performed immunophenotyping of the decidua basalis and decidua parietalis to determine whether exhausted and senescent T cells are present at the maternal-fetal interface and whether the presence of pathological (i.e., preterm) or physiological (i.e., term) labor and/or placental inflammation alter such adaptive immune cells. In addition, decidual exhausted T cells were sorted to test their functional status. We found that (1) exhausted and senescent T cells were present at the maternal-fetal interface and predominantly expressed an effector memory phenotype, (2) exhausted CD4+ T cells increased in the decidua parietalis as gestational age progressed, (3) exhausted CD4+ and CD8+ T cells decreased in the decidua basalis of women who underwent labor at term compared to those without labor, (4) exhausted CD4+ T cells declined with the presence of placental inflammation in the decidua basalis of women with preterm labor, (5) exhausted CD8+ T cells decreased with the presence of placental inflammation in the decidua basalis of women who underwent labor at term, (6) both senescent CD4+ and CD8+ T cells declined with the presence of placental inflammation in the decidua basalis of women who underwent preterm labor, and (7) decidual exhausted T cells produced IFNγ and TNFα upon in vitro stimulation. Collectively, these findings indicate that exhausted and senescent T cells are present at the human maternal-fetal interface and undergo alterations in a subset of women either with labor at term or preterm labor and placental inflammation. Importantly, decidual T cell function can be restored upon stimulation.

Visualizing Dynamic Changes at the Maternal-Fetal Interface Throughout Human Pregnancy by Mass Cytometry

“…This provided an unbiased, data-driven overview of all decidual immune cell populations throughout pregnancy. Previously described decidual immune cell subsets (5,33,45,46) and the kinetics of the major immune cell lineages during gestation (5,6,47) were validated in the current study. Moreover, we observed unprecedented immune cell heterogeneity in the decidua.…”

Regulatory T Cells Play a Role in a Subset of Idiopathic Preterm Labor/Birth and Adverse Neonatal Outcomes

“…To further explore the mechanisms whereby the loss of Tregs induces adverse perinatal outcomes, we explored the cellular repertoire at the maternal-fetal interface, in the placenta, and in the maternal circulation. This research question was based on previous studies showing that PTL involves stereotypical cellular responses at the maternal-fetal interface ( Arenas-Hernandez et al, 2016 , 2019 ; St Louis et al, 2016 ; Xu et al, 2016 ; Gomez-Lopez et al, 2017a ; Rinaldi et al, 2017 ; Garcia-Flores et al, 2018 ; Xu et al, 2018 ; Leng et al, 2019 ; Slutsky et al, 2019 ), in the placenta ( Salafia et al, 1991 ; Redline and Patterson, 1994 ; Kim et al, 2009 , 2015b ; Gill et al, 2019 ), and in the maternal circulation ( Gervasi et al, 2001 ; Pique-Regi et al, 2019 ). Foxp3 DTR dams underwent partial or total depletion of Tregs, and the decidua, myometrium, placenta, and peripheral blood were collected in preterm gestations.…”

Pathogenesis of preterm birth: bidirectional inflammation in mother and fetus

“…Effector memory CD4 + and CD8 + T cells are also enriched in the decidua in spontaneous PTL, suggesting the inflammatory potential of these cells is greater in PTL women [73]. CD4 + and CD8 + T cells expressing "exhausted" (PD-1 + TIM-3 + CTLA4 − LAG-3 − ) and "senescent" (KLRG-1 + CD57 + ) memory and effector phenotypes were identified in the decidua of women with term and preterm labor [66]. Notably, the proportions of exhausted CD4 + T cells increased in the decidua parietalis with increasing gestational age but declined in the decidua basalis of women who underwent PTL with placental inflammation.…”

“…Notably, the proportions of exhausted CD4 + T cells increased in the decidua parietalis with increasing gestational age but declined in the decidua basalis of women who underwent PTL with placental inflammation. As TNFα and interferon (IFN)γ production could be induced ex vivo in the exhausted T cells, these cells may restore their effector function upon placental inflammation [66].…”