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

In the intestine, peripherally induced regulatory T (pTreg) cells play an essential role in suppressing inflammatory responses to food proteins. However, the identity of the antigen-presenting cells that instruct food-specific pTreg cells is poorly understood. 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 their presence underlies the phenomenon of oral tolerance. A wave of TC IV differentiation in the periweaning period was associated with a window of opportunity for enhanced pTreg cell 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. CITE-seq (gene expression and HTOs) of CD45+Lin–RORgt+CXCR6-MHCII+ cells from lymph nodes of 2-week-old Rorc_Venus-creERT2 pooled from 7 biological replicates.