Summary
Intestinal epithelial cells (IECs) act as a physical barrier separating the commensal-containing intestinal tract from the sterile interior. These cells have found a complex balance allowing them to be prepared for pathogen attacks while still tolerating the presence of bacteria and viral stimuli present in the lumen of the gut. Using primary human IECs we probed the mechanisms used by cells to maintain this tolerance. We discovered that stimuli emanating from the basolateral side of IECs elicited a strong induction of the intrinsic immune system as compared to lumenal apical stimulation. Additionally, we determined that this controlled apical response was driven by the clathrin-sorting adapter AP-1B. Mice and human IECs lacking AP-1B showed an exacerbated immune response following apical stimulation. Together these results suggest a model where the cellular polarity program plays an integral role in the ability of IECs to tolerate apical commensals and detect/fight invasive basolateral pathogens.