Helicobacter Pylori Elicits B7-H3 Expression on Gastric Epithelial Cells: Implications in Local T Cell Regulation and Subset Development During Infection
2019
Helicobacter pylori (H. pylori) is a gram-negative bacterium that infects more than 50% of humanity and is
associated with gastritis, peptic ulcer and gastric cancer. Although CD4+ T cells are recruited to the gastric
mucosa, the host is unable to clear the bacteria. Previously, we demonstrated that H. pylori infection
upregulates the expression of the T cell co-inhibitory molecule B7-H1 while simultaneously downregulating
the expression of T cell co-stimulatory molecule B7-H2 on gastric epithelial cells (GEC), which together
affect the Treg and Th17 cell balance and foster bacterial persistence. Because B7-H3, another member of
the B7 family of co-inhibitory receptors, has been found to have important immunoregulatory roles and in
cancer, in this study we examined the expression of B7-H3 molecules on GEC and how the expression is
regulated by H. pylori during infection. Our study showed that both human and murine GEC constitutively
express B7-H3 molecules, but their expression levels increased during H. pylori infection. We further
demonstrated that H. pylori uses its type 4 secretion system (T4SS) components CagA and cell wall
peptidoglycan (PG) fragment to upregulate B7-H3. Th17 cells and Treg cells which are increased during H.
pylori infection also had an effect on B7-H3 induction. The underlying cell signaling pathway involves
modulation of p38MAPK pathway. Since B7-H3 were shown to up-regulate Th2 responses, the phenotype
of T cell subpopulations in mice infected with H. pylori PMSS1 (contains functional T4SS) or SS1 (cannot
deliver CagA into GEC) strains were characterized. A mixed Th1/Th2 response in H. pylori infected mice
was observed. Consistent with previous findings, increased Treg cells and decreased Th17 cells in MLN of
PMSS1 infected mice compared to SS1 infected mice was observed. Human biopsy samples collected from
gastritis biopsies and gastric tumors showed a strong association between increased B7-H3 and Th2
responses in H. pylori strains associated with gastritis. T cell: GEC co-cultures and anti-B7-H3 blocking Ab
confirmed that the induction of Th2 is mediated by B7-H3 and associated exclusively with an H. pylori
gastritis strain not cancer or ulcer strains. In conclusion, these studies revealed a novel regulatory
mechanism employed by H. pylori to influence the type of T cell response that develops within the infected
gastric mucosa.
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