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Helicobacter pylori modulates NOTCH signaling to orchestrate host immunity

Karen Zhang, Dr. Alex G Peniche, Dr. Victor E Reyes

University of Texas Medical Branch

Introduction: Helicobacter pylori (Hp) bacteria infect more than 50% of the world’s population and causes important gastric diseases in different patients, including gastritis, peptic ulcer disease, and gastric adenocarcinoma. It is not clear what determines the disease induced by the infection. A hallmark of Hp is its ability to hijack the immune response to evade clearance to establish chronic infection. T cells differentiation is influenced by Hp. T regulatory (Treg) cells are immunosuppressive and found in the Hp-infected gastric mucosa and various tumors, presumably to escape immune surveillance. Notch receptors/ligands play key roles in differentiation in T cells, but their involvement in Hp pathogenesis is unknown. We hypothesize that Hp influences Notch receptors and ligands to affect local T cell phenotype and function. To test this, we examined their expression by gastric epithelial cells (GEC) infected with Hp isolates from different gastric diseases. Methods: N87 GEC line or human gastric organoids were infected with Hp isolates from different gastric diseases and co-cultured with naïve human T cells. After culture, the cells were examined by flow cytometry and qPCR for the expression of Notch receptors and ligands. T cells were characterized for their expression of markers characteristic of various CD4+ T cell subsets. Because Notch4 expression by GEC infected with Hp from gastric cancer was significantly increased, siRNA was used to knockdown Notch4 receptor on N87 GEC line before co-culture with T cells, which were phenotyped by flow cytometry. Results: Hp isolates from gastric cancer cases stimulated higher expression of Notch 4 and Dll4 ligand by GEC than Hp isolates from peptic ulcer disease and gastritis. Interestingly, GEC infected with gastric cancer Hp isolates also induced significantly more Treg cells than GECs infected with other isolates. The siRNA knockdown of Notch4 in GEC infected by gastric cancer Hp isolates dramatically reduced the frequency of Treg cells induced in those co-cultures. Conclusion: These results suggest that Hp from gastric cancer differ from isolates from other gastric diseases in their ability to induce Treg cells and Notch4 expression. Further, our data point to a mechanistic role of Notch4 in Treg induction by Hp gastric cancer isolates. These results may pave the way for translational studies targeting Hp-associated gastric cancer, which has an associated global mortality of close to a million people worldwide.

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