The Role of the GPR15-C10ORF99 Pathway in T cell Homing during Eosinophilic Esophagitis

PROJECT SUMMARY/ABSTRACT Eosinophilic Esophagitis (EoE) is a chronic inflammatory disease characterized by eosinophilic infiltration of the esophagus, esophageal dysfunction, and progressive fibrosis. EoE is the most common cause of dysphagia, esophageal perforation, and food impaction. The annual cost of EoE in the United States is estimated to be in the range of $1 billion, and its prevalence is currently approaching that of inflammatory bowel disease. However, little is known about how EoE occurs, and the diagnostic approach involves highly invasive procedures. Currently, available treatments include topical steroid therapy or dietary elimination, though achieving the long-term efficacy of the former and regularly avoiding particular foods can present challenges. Therefore, understanding how EoE occurs is essential to developing a more effective diagnostic and treatment approach for EoE. Research to date indicates that T helper type 2 (Th2) cells reacting to specific food antigens likely cause EoE and that the symptoms are limited to the esophagus. Therefore, it is likely that Th2 cells that migrate specifically to the esophagus mediate the symptoms. Indeed, recent research has shown that the esophageal biopsies of active EoE patients contain Th2 cells, which express a molecule called GPR15. Our group first discovered that GPR15 is a receptor necessary for T cells to migrate to the large intestine. Furthermore, we found that a molecule known as C10ORF99 in the large intestine functions as a ligand for GPR15 to complete the migration. Additionally, publicly accessible databases demonstrated the high expression of C10ORF99 in the esophagus. Therefore, the GPR15-C10ORF99 combination may mediate T cell homing to the esophagus and pathogenesis during EoE. In that case, GPR15 and C10ORF99 may be useful diagnostic markers and therapeutic targets for EoE. In this proposal, we aim to determine whether the GPR15-C10ORF99 pair is required for T cell homing to the esophagus and EoE pathology. We are in a unique position to answer these important questions because we have extensive experience with the GPR15-C10ORF99 pathway, useful molecular genetic tools to study their functions in EoE mouse models, and preliminary results to support our hypotheses.