Identification and characterization of dietary antigens in oral tolerance

Food antigens elicit immune tolerance through the action of intestinal regulatory T (T_reg) cells. Unlike food allergens, the proteins that mediate tolerance are mostly undescribed. Here, we found that epitopes derived from seed storage proteins are targets of murine intestinal T_reg cells, with the most frequent response targeting the C terminus of the maize protein alpha-zein. A major histocompatibility complex (MHC) tetramer loaded with this antigen revealed that zein-specific T cells are predominantly intestinal T_reg cells, develop concurrently with weaning, and constitute up to 2% of the peripheral T_reg cell pool. Zein-responsive T_reg cells repressed naïve T cell proliferation ex vivo, and prior dietary exposure resulted in a constrained response upon diverse inflammatory challenges in vivo, supporting a specific role for gut-resident T_reg cells in suppressing systemic immune responses. Our work reveals the development, immune-suppressive characteristics, and function of naturally occurring T_reg cells that recognize dietary seed storage proteins, a previously undescribed class of antigens in oral tolerance.