Type 1 Regulatory T cells induced by intestinal epithelial cells respond to food antigen

As the first-line barrier against food antigens, the intestinal epithelium’s role in establishing peripheral immune tolerance to food remains completely unknown. Additionally, the specific types of regulatory T cells induced to maintain food tolerance—along with their antigen specificity—are still unclear. Here we found small intestinal FOXP3 ^- IL-10 ⁺ Tr1 cells, but not Treg cells, can respond to food antigens presented by intestinal epithelial cells (IECs) in an antigen-specific manner. Through immunopeptidome analysis of MHCII-presented peptides, we demonstrate that IECs can present food-derived antigens. Importantly, these IEC-presented food antigens are exclusively recognized by the TCR repertoire of small intestinal Tr1 cells, not Treg cells. Furthermore, we show that T cells recognizing IEC-presented food antigens specifically differentiate into Tr1 cells in the siLP. These findings establish two key insights: first, that maintaining food tolerance represents a physiological function of Tr1 cells, and second, that IECs play a central role in maintaining food tolerance. Our work thus provides mechanistic understanding of how the intestinal epithelium contributes to immune tolerance through its antigen presentation capacity and subsequent Tr1 cell induction.