A wave of Thetis cells imparts tolerance to food antigens early in life.

Within the intestine, peripherally-induced regulatory T (pTreg) cells play an essential role in suppressing inflammatory responses to food proteins. However, the identity of antigen-presenting cells (APC) that instruct food-specific pTreg cells is poorly understood. Here, we found that a subset of Thetis cells, TC IV, is required for food-specific pTreg cell differentiation. TC IV were almost exclusively present within mesenteric lymph nodes suggesting that the presence of TC IV underlies the phenomenon of oral tolerance. A wave of TC IV differentiation in the peri-weaning period was associated with a window of opportunity for enhanced pTreg generation in response to food antigens. Our findings indicate that TC IV may represent a therapeutic target for the treatment of food-associated allergic and inflammatory diseases.