Coordinated network of T cells and antigen presenting cells regulate tolerance to food

To efficiently absorb nutrients and facilitate microbial commensalism, the host establishes tolerogenic immune programs against dietary and commensal antigens, promoted by peripheral regulatory T cells (pTregs)1,2. Previous research into which antigen-presenting cells (APCs) initiate dietary pTreg responses focused on type 1 DCs (cDC1)3. However, we now report that food-specific pTreg cells are exclusively induced by the recently identified RORγt+ APCs4–8, and not by cDC1. Instead, pTregs interact with cDC1 to regulate the response of food-specific CD8αβ T cells that accumulate in the lamina propria (LP) and epithelial layer of the small intestine (SI) and express memory markers. Upon infection with pathogens that mimic dietary antigens, food-specific CD8αβ cells activate an effector program to potentially guard against ‘Trojan horse’ attacks. Uniquely, after the infection resolves, these cells do not respond to their corresponding dietary antigens, allowing for safe food consumption. Based on our findings, we propose that in response to dietary antigens, dedicated antigen-presenting cells direct a unique CD8αβ response that is coupled to the pTreg program to facilitate protective acute effector responses within the overall strategy of tolerance.