Highly differentiated IL5+ Th2 cells in food allergy and eosinophilic GI disease

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Eosinophilic gastrointestinal disorders (EGIDs) are a group of food allergy related diseases characterized by eosinophilic inflammation of the gastrointestinal tract. In the past 20 years, there has been a dramatic increase in the incidence of EGIDs, particularly eosinophilic esophagitis (EoE), but also eosinophilic gastroenteritis (EGE). EGID patients often have numerous food hypersensitivities, and the disease goes into remission with the institution of an amino acid based allergen-free elemental diet. In sum, this suggests that EGID is a food allergen driven eosinophilic inflammatory gut disease. In our previous work, we have demonstrated that IL-5+ Th2 cells are associated with EGID (eosinophilic food allergy), but not anaphylactic forms of food allergy. We have further characterized these IL-5+ Th2 cells as more highly differentiated Th2 cells that are the product of multiple rounds of antigenic stimulus. Other research groups working with mouse models of allergic inflammation have identified similar IL-5+ Th2 cells as having greater pro-inflammatory function. These IL-5+ Th2 cells have been termed pathogenic effector Th2 (peTh2) cells to emphasize their function in causing disease. In sum, these findings suggest that food allergen-driven IL-5+ peTh2 cells are the major pathway driving allergic eosinophilic inflammation. In the past year we have characterized phenotypic markers for these peTh2 cells, which facilitate both functional studies as well as their identification in tissue samples. The combination of the well-described Th2 marker CRTH2 with either hematopoietic prostaglandin synthase (hPGDS) or CD161 identified an IL-5 bright CD4 T cell population. In both EGID and atopic dermatitis, the frequency of these peTh2 cells was tightly correlated to peripheral blood eosinophil count, suggesting that this cell population is driving blood eosinophilia. Additionally, we have shown that IL-5+ Th2 express gut tissue homing receptors and home to gut tissue in EGID. In a variety of assay systems, peTh2 cells have greater functional activity than IL-5- Th2 cells. This indicates that the peTh2 subpopulation is a major Th2 population driving allergic eosinophilic inflammation. We have also shown that Th2 cells, and in particular peTh2 cells, are highly sensitive to molecular target of rapamycin (mTOR) inhibitors, such as rapamycin and Torin 1. Rapamycin inhibition of proliferation is significantly greater for IL-5+ peTh2 vs. either IL-5- Th2 or Th1 cells, at concentrations ranging from 0.25-10 nM. IL-5+ Th2 cells demonstrated enhanced S6 ribosomal protein phosphorylation, indicating that the mTORC1 pathway is preferentially activated in this subpopulation. The key role of the mTORC1 pathway in peTh2 cell proliferation was confirmed using RNA inhibition of mTORC1 pathway genes. These results demonstrate that peTh2 cells are highly metabolically active and as such have upregulated the mTORC1 pathway. This mTORC1 upregulation by peTh2 cells results in their greater sensitivity to mTOR inhibitors.