Premature Treg induction in early life results in FoxP3 instability post-weaning

Abstract

Abstract Peripherally-derived RORγt+ regulatory T cells (Tregs) induced in early life are crucial for maintaining oral tolerance later in life, and the loss of these long-lived cells is associated with increased allergic and inflammatory phenotypes in several animal models. We have identified a predominant pathway of luminal antigen delivery that is associated with Treg development. Around weaning, microbial and dietary proteins are delivered to the colonic lamina propria via goblet cell-associated antigen passages (GAPs) and taken up by antigen presenting cells. GAP formation is inhibited by breastmilk-derived epidermal growth factor (EGF) which is highest in maternal milk at parturition and is diminished by weaning. We have previously shown that disruption of this process – via EGF receptor inhibition (EGFRi) day of life (DOL)4–8 or by conditional deletion of EGFR from goblet cells – results in premature antigen delivery. Consequently, this results in an early initial increase in FoxP3 expression in the colon that is unstable and, ultimately, lost by Tregs primed pre-weaning; this suggests that earlier education of T cells is incompatible with regulatory T cell differentiation in early life. EGFRi-treated FoxP3eGFP-Cre-ERT2ROSAlsl-YFPmice, whose FoxP3+ cells were YFP-labeled at DOL21, had a larger number of YFP+ T cells that lost FoxP3 expression than that of control mice, by DOL28. Further, compared to controls, wild-type mice treated with EGFRi DOL4–8 had increased IFNγ, TNFα, and IL-17a-expressing CD4 T cells when challenged with DSS colitis later in life. This suggests that early antigen delivery-associated FoxP3 instability may contribute to an increased propensity toward an inflammatory phenotype later in life.