A coordinated cellular network regulates tolerance to food

To absorb nutrients and support commensal microbes, the host induces tolerogenic immune responses via peripheral regulatory T cells (pTregs) 1,2 . Prior studies identified type 1 dendritic cells (cDC1) as initiators of dietary pTregs 3 . However, we now report that food-specific pTreg cells are exclusively induced by the recently identified RORγt APCs 4–8 and not by cDCs. Instead, our data suggest that pTreg–cDC1 interactions in steady-state limit the expansion of food-specific CD8αβ T cells. This regulation breaks during 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 (APCs) 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.