A coordinated cellular network regulates tolerance to food.

To absorb nutrients and support commensal microorganisms, the host induces tolerogenic immune responses through peripheral regulatory T (pT(reg)) cells(1,2). Previous studies identified conventional type 1 dendritic cells (cDC1s) as initiators of dietary pT(reg) cells(3). However, here we report that food-specific pT(reg) cells are induced exclusively by the recently identified RORγt antigen-presenting cells(4-8) and not by conventional dendritic cells. Instead, our data suggest that pT(reg) cell-cDC1 interactions during homeostasis limit the expansion of food-specific CD8αβ T cells. This regulation is disrupted by infection or food poisoning, enabling dietary CD8αβ T cells to expand and acquire effector functions in response to mimicked food antigens. Unlike in typical infections, after the pathogen is cleared, dietary CD8αβ T cells do not expand in response to their corresponding dietary antigens. Thus, we propose that, in response to dietary antigens, tolerance is mediated by a circuit of dedicated antigen-presenting cells and T cells. When the host is challenged by infection, this circuit permits the transient expansion of protective effector responses without compromising the overall strategy of tolerance that ensures safe food consumption.