Human regulatory T cell physiology - Lessons learnt from newborns and adults

Abstract

Human Regulatory T (Treg) cells play a critical role in the immune homeostasis. Hence, understanding Treg cell physiology is of vital importance. Various soluble factors, including IL-10 and short chain fatty acids (SCFAs), contribute to the transplacental immune programming by shaping the fetal immune system, specifically Treg cells. Therefore, this thesis aims to provide further evidence for the Treg cell transplacental programming, and to explain how SCFAs contribute to this process. We demonstrated that the absence of maternal gut microbiota caused significantly reduced fetal thymus size and fewer thymic Foxp3+ Treg cell numbers, which could be rescued by supplementation of acetate. Moreover, the fetal-maternal correlation of serum acetate implied that maternal acetate likely crossed the placenta. TCR sequencing data also suggested that fetal antigen receptor immunity was not inherited, but rather driven by local immunomodulatory factors. Taken together, it indicated that maternally acquired metabolites (acetate) play an important role in shaping fetal thymic development and output, hence exerting their influences on fetal immunity. In addition to the context of pregnancy, this thesis extends the knowledge of SCFAs to both neonate and adult immune cells in vitro. We are the first to demonstrate the effectiveness of SCFAs in Treg cell differentiation via histone acetylation inhibition in vitro in humans. We also proved the tolerogenic effects of SCFAs on other immune cells in humans, including MoDCs and different T cell subsets. These results highlight the essential role of SCFAs in immune tolerance, particularly in Treg cell physiology. Collectively, this study provides theoretical evidence for a non-pharmaceutical approach. Since diet is closely interlinked with the composition of gut microbiota and SCFAs production, dietary interventions may alleviate or treat allergies and autoimmune diseases via modulating Treg cells.