The oesophagus as an immune organ

Abstract

The oesophagus has traditionally been viewed as a simple conduit for food transport. In performing this delivery function, it confronts a continuous influx of foreign antigens, including food particles with variable microbial content, and encounters many biophysical stimuli triggered by food textures and temperature. To meet these challenges, the oesophagus comprises a robust barrier featuring a thick, multilayered epithelium coated by mucins and mechanically held together by strong adhesion complexes, including desmosomal junctions. Sentinel immune cells, including a notable presence of CD8⁺ resident memory T cells, mast cells and dendritic cells, are abundant alongside IL-1 family cytokines released and activated under tight homeostatic regulation through a balance of proteases and antiproteases. Pattern recognition receptors, such as Toll-like receptors on epithelial cells, identify foreign antigens and can trigger cytokine release. Disruptions, whether acquired or genetically inherited, in these innate immune functions contribute to disease onset. Here, we present evidence that the oesophagus is an immune organ with extensive sensing properties designed to tolerate and mount defences against antigenic and biophysical challenges.

Figure 1

Summary of the innate immune components of the homeostatic esophagus. TGF-β, transforming growth factor beta; TLRs, Toll-like receptors.

Figure 2

The schematic illustrates the innate immune components of the homeostatic esophagus, depicting representative molecules, cells, and pathways involved in maintaining barrier integrity and immune balance. Pattern recognition receptors (PRRs) and the aryl hydrocarbon receptor (AHR) sense the esophageal environment by detecting microbial-associated molecular patterns, dietary metabolites, and xenobiotics, influencing local immune responses, barrier integrity, and epithelial homeostasis. Structural crosslinked proteins are more prevalent in differentiated epithelial cells. Notably, the TGF-β pathway is likely operational in the basal layer of the epithelium, where TSLP and IL-1 cytokines, like IL-33, are also expressed during inflammation. The zoomed-in image of epithelial cells on the right highlights the proteolytic imbalance in eosinophilic esophagitis (EoE), characterized by elevated CAPN14 and decreased SPINK7 expression, which leads to increased activity of KLK5. This imbalance compromises the epithelial barrier and activates the pro-inflammatory receptor PAR2, resulting in the release of alarmins such as TSLP. CAPN14, calpain 14; DSG1, desmoglein 1; IFNγ, interferon gamma; IκBα, NFκB inhibitor alpha; IL-1, interleukin 1; ILC2, innate lymphoid cell type 2; KLK5, kallikrein 5; NF-κB1, nuclear factor kappa B 1; PADI, peptidyl arginine deiminase; PAR2, protease-activated receptor 2; RipIL-33, ripoptosome IL-33; TSLP, thymic stromal lymphopoietin; SPINK7, serine peptidase inhibitor Kazal type 7; TGF-β, transforming growth factor beta; TGM, transglutaminase.