Cheifetz, Talia Raitt

Summary Oral tolerance promotes the suppression of immune responses to innocuous antigen and is primarily mediated by regulatory T cell (Tregs). The development of oral tolerance begins in early life during a “window of tolerance,” which occurs around weaning and is mediated by components in breastmilk. Herein, we review the factors dictating this window and how Tregs are uniquely educated in early life. In early life, the translocation of luminal antigen for Treg induction is primarily dictated by goblet cell‐associated antigen passages (GAPs). GAPs in the colon are negatively regulated by maternally‐derived epidermal growth factor and the microbiota, restricting GAP formation to the “periweaning” period (postnatal day 11–21 in mice, 4–6 months in humans). The induction of solid food also promotes the diversification of the bacteria such that bacterially‐derived metabolites known to promote Tregs—short‐chain fatty acids, tryptophan metabolites, and bile acids—peak during the periweaning phase. Further, breastmilk immunoglobulins—IgA and IgG—regulate both microbial diversity and the interaction of microbes with the epithelium, further controlling which antigens are presented to T cells. Overall, these elements work in conjunction to induce a long‐lived population of Tregs, around weaning, that are crucial for maintaining homeostasis in adults.

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-YFP mice, 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.