Thetis cells: regulators of intestinal immune tolerance

Our body's mucosal surfaces interface with the external environment and are potential sites of entry for pathogens as well as noxious substances. Yet, these barrier sites are also colonized with symbiotic microbes and are in contact with harmless environmental antigens. Different barrier epithelia harbor distinct microbial communities that shape both the epithelial layer and local immune cells that maintain tissue homeostasis and tolerance to symbiotic microbes. This seemingly paradoxical peaceful co-existence of immune cells and microbes has fascinated immunologists for decades: how does the immune system balance inflammatory and tolerogenic responses? The mechanisms underlying peripheral immune tolerance to harmless foreign antigens have been most widely studied within the intestine, where the immune system must establish and maintain tolerance to harmless food and commensal antigens. Dysregulated immune responses to these antigens are linked to several human diseases, including inflammatory bowel disease, celiac disease, and food allergy. Understanding the cellular and molecular cues that promote intestinal immune tolerance is key to the development of effective therapeutic strategies for these pathologies. Here, we review recent insights into mechanisms of intestinal tolerance with a focus on recently identified RORγt⁺ antigen-presenting cells.