REGulatory T Cells in Autism Induced by Maternal Immune Activation

Autism Spectrum Disorders (ASD) represent a heterogeneous clinical entity of neurodevelopmental disorders affecting around 1% of the general population (Lord et al. 2020). There is currently no curative treatment for patients with ASD, and management does not take into account the existence of specific patient subgroups. Beyond genetic factors (Delorme et al. 2013), environmental factors play a fundamental role in the determinism of ASD. Among them, maternal immune activation (MIA) during pregnancy is a recognized risk factor for ASD in children (Estes and McAllister 2016). Our team has helped to demonstrate that MIA induced by infections or autoimmune pathologies in the mother during pregnancy (particularly at the end of the 1st trimester/beginning of the 2nd trimester) significantly increases the risk of ASD in the offspring (Antoun et al. 2021). Mechanistically, MIA leads to a deregulation of the regulatory T lymphocyte (Tregs)/Th17 balance (in the direction of a decrease in anti-inflammatory Tregs and an increase in pro-inflammatory Th17) in the mother but also, via epigenetic mechanisms, in the fetus (Lim et al. 2021). Our team have recently demonstrated the same Tregs/Th17 deregulation profile in ASD patients (Ellul et al. 2021). This disruption of the Tregs/Th17 balance is responsible for disrupting fetal brain development via IL-17 receptors present on fetal neurons (Choi et al. 2016). Importantly, these socio-communicative and morphological abnormalities appear, in specific animal models, to be reversible upon restoration of the Tregs/Th17 balance (Z. Xu et al. 2021; Choi et al. 2016). While data on the involvement of IL-17 are becoming better known, the role of Tregs in this model has been surprisingly little studied.Our overall aim is therefore, in humans and mice, to determine the role of Tregs and IL-17-producing lymphocytes in the development and maintenance of autistic symptoms triggered by MIA. Our specific objectives in humans will be to use an exi