Oral Virtual Presentation (Virtual only) ESA-SRB-ANZBMS 2021

Proinflammatory phenotypic plasticity of maternal regulatory T cells precedes interleukin 1β-induced preterm birth in mice (#106)

Jessie R Walker 1 , Ella S Green 1 , Peck Y Chin 1 , Lachlan M Moldenhauer 1 , Sarah A Robertson 1
  1. Robinson Research Institute & School of Biomedicine, University of Adelaide, Adelaide, SA, Australia

Maternal immune system dysfunction, notably deficient CD4+Foxp3+ regulatory T (Treg) cells, are implicated in the pathophysiology of preterm birth (PTB). During parturition there is a relative shift away from immune tolerance towards proinflammatory T cell responses. However, the role of Treg cells in parturition is ill-defined. Given that Treg cells exhibit plasticity and adopt T effector-like functions in inflammatory environments, we hypothesised that preterm parturition may be exacerbated by maternal Treg cells with an aberrant inflammatory phenotype or reduced lineage stability. To investigate this, we characterised Treg cells in physiological parturition and sterile inflammation-induced PTB. Female C57Bl/6 mice mated to BALB/c males were administered 6µg interleukin 1β (IL1β) (or vehicle, n=11 mice/group) on gestational day (GD) 15.5 to induce PTB. T cells in the uterus-draining lymph nodes were assessed by flow cytometry on GD16.5, approximately four hours prior to preterm delivery. Mice administered IL1β had expanded T cell populations prior to labour (P<0.010). Treg cell-specific upregulation of activation maker CD25 (P<0.001) and an increased ratio of Treg cells to proinflammatory IFNγ+ T effector cells (P<0.050) suggested an activated Treg cell population may constrain inflammation ahead of PTB. However, there was a subset of Treg cells expressing heightened levels of inflammatory trafficking receptor CCR6 and proinflammatory cytokine IL17A (P<0.050). Using a mouse model that reports Foxp3+ Treg cell lineage, we showed that the number of Treg and so-called “exTreg” cells that had lost expression of Foxp3 was unchanged over GD16.5-18.5, suggesting stability of Treg cells is maintained in normal late gestation. Interestingly, decreased CD4+ T cell expression of master regulator Tbet was evident in physiological late gestation in the lineage tracing mice (P<0.010), and in the PTB cohort (P<0.050). Ongoing studies will investigate the lineage stability of Treg cells prior to PTB, and the significance of modulated Tbet expression during parturition.