Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

A reduced activation and suppression phenotype in Treg cells correlates with insulin resistance in recurrent pregnancy loss patients (#12)

Lachlan M Moldenhauer 1 , Sarah Linthwaite 2 , Kerrie L Foyle 1 , David J Sharkey 1 , Catherine D McCormack 1 2 , Louise Hull 1 2 , Sarah A Robertson 1
  1. Robinson Research Institute, Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia
  2. Women's and Children's Hospital, Adelaide, SA, Australia

Recurrent miscarriage (RM), defined as 2 or more early pregnancy losses, affects 1-2% of women, with 50% of cases having no identifiable cause. An emerging likely aetiology is a dysfunctional immune system and impaired immune tolerance to pregnancy. Specifically, a deficiency in CD4+ T regulatory (Treg) cells can lead to failed maternal immune tolerance and compromised embryo implantation. One factor that can trigger Treg cell insufficiency in other clinical settings is insulin resistance. Given insulin resistance is a notable risk factor for RM, we aimed to determine if insulin resistance in RM patients is linked with altered Treg cell abundance and phenotype. Women with at least 2 miscarriages were recruited from the Women’s and Children’s Hospital, Adelaide (n=59). At least 6 weeks post-miscarriage, in the mid-luteal phase of the menstrual cycle, women underwent a fasting blood test to assess glucose and insulin concentrations, from which Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was calculated. Patients with a HOMA-IR ≥ 3.0 were considered insulin resistant. T cells were isolated from blood samples and their abundance and phenotype, including proliferation, memory, and suppressive capacity, were analysed by multi-coloured flow cytometry. Linear regression analysis revealed that insulin resistance was correlated to a decrease in the abundance of highly suppressive CTLA4+HLADR+Helios+ Treg cells and decreased Treg cell proliferation. Patients with insulin resistance also had an increased proportion of CD45RA+CCR7+ naïve Treg cells, and a correlating decrease in effector memory and central memory Treg cells. These effects were most evident in women whose last miscarriage was of a genetically normal embryo. Insulin resistance in RM patients was associated with fewer activated, proliferating and memory Treg cells in the peripheral blood. We conclude that curtailed activation of the Treg cell population may impair functional immune tolerance and contribute to recurrent miscarriage susceptibility.