Thetis cells induce food-specific Treg cell differentiation and oral tolerance

The intestinal immune system must establish tolerance to food antigens to prevent onset of allergic and inflammatory diseases. Peripherally generated regulatory T (pTreg) cells play an essential role in suppressing inflammatory responses to allergens; however, the antigen-presenting cell (APC) that instructs food-specific pTreg cells is not known. Here, we show that antigen presentation and TGF-β activation by a subset of RORγt ⁺ antigen-presenting cells (APC), Thetis cells IV (TC IV), is required for food-induced pTreg cell differentiation and oral tolerance. By contrast, antigen presentation by dendritic cells (DCs) was dispensable for pTreg induction but required for T _H 1 effector responses, highlighting a division of labor between tolerogenic TCs and pro-inflammatory DCs. While antigen presentation by TCs was required for food-specific pTreg generation both in early life and adulthood, the increased abundance of TCs in the peri-weaning period was associated with a window of opportunity for enhanced pTreg differentiation. These findings establish a critical role for TCs in oral tolerance and suggest that these cells may represent a key therapeutic target for the treatment of food-associated allergic and inflammatory diseases.