Intestinal epithelial cells (IECs) lining the surface of our gastrointestinal tract have their apical sides in constant contact with the lumenal commensal flora. As such, IECs are faced with a major challenge as they must tolerate the presence of the microbiota while maintaining full responsiveness against enteric pathogens. How IECs achieve such tailored immune response remains unclear but it is known that an inappropriate response against the microbiota participates in inflammatory bowel diseases. Here we identify and characterize the IECs-specific molecular mechanisms that govern this unique immune response and ultimately lead to gut immune homeostasis.
Using human mini-gut organoids and human intestinal epithelial cell (hIECs) lines we found that primary non-transformed hIECs assemble a polarized immune response against enteric pathogens (bacterial and viral). Not only do hIECs secrete cytokines and interferons (IFNs) in a polarized manner (apical vs. basolateral secretion), hIECs can mount a distinct immune response as a function of infection side. Enteric pathogen infection of hIECs from their apical side (lumenal side) leads to an acute production of both type I and type III IFNs which is quickly downregulated. On the contrary, infection from their basolateral sides (lamina propia side) triggers a stronger innate immune response characterized by prolonged production of type III IFNs. We demonstrated that this polarized immune response is dependent on the polarized nature of hIECs. We identified the clathrin/AP1-dependent polarity program as a specific regulator of TLR3 signaling allowing hIECs to mount a moderate immune response against apical challenges and a strong immune response against basolateral stimulation. Interestingly, mice lacking AP1 display colitis due to an over-reaction to their microbiota.
This polarized response would represent a strategy to maintain gut immune homeostasis by avoiding excessive response against microbes located in the lumenal side while maintaining full responsiveness against invasive pathogens that have passed the epithelium barrier.