Programmed Death Ligand 1-Expressing Classical Dendritic Cells Mitigate Helicobacter-Induced Gastritis

BACKGROUND & AIMS: Helicobacter pylori has been reported to modulate local immune responses to colonize persistently in gastric mucosa. Although the induced expression of programmed cell death ligand 1 (PD-L1) has been suggested as an immune modulatory mechanism for persistent infection of H pylori, the main immune cells expressing PD-L1 and their functions in Helicobacter-induced gastritis still remain to be elucidated. METHODS: The blockades of PD-L1 with antibody or PDL1-deficient bone marrow transplantation were performed in Helicobacter-infected mice. The main immune cells expressing PD-L1 in Helicobacter-infected stomach were determined by flow cytometry and immunofluorescence staining. Helicobacter felis or H pylori-infected dendritic cell (DC)-deficient mouse models including Flt3(-/-), Zbtb46-diphtheria toxin receptor, and BDCA2-diphtheria toxin receptor mice were analyzed for pathologic changes and colonization levels. Finally, the location of PD-L1-expressing DCs and the correlation with H pylori infection were analyzed in human gastric tissues using multiplexed immunohistochemistry. RESULTS: Genetic or antibody-mediated blockade of PD-L1 aggravated Helicobacter-induced gastritis with mucosal metaplasia. Gastric classical DCs expressed considerably higher levels of PD-L1 than other immune cells and co-localized with T cells in gastritis lesions from Helicobacter-infected mice and human beings. H felis- or H pylori-infected Flt3(-/-) or classical DC-depleted mice showed aggravated gastritis with severe T-cell and neutrophil accumulation with low bacterial loads compared with that in control mice. Finally, PD-L1-expressing DCs were co-localized with T cells and showed a positive correlation with H pylori infection in human subjects. CONCLUSIONS: The PD-1/PD-L1 pathway may be responsible for the immune modulatory function of gastric DCs that protects the gastric mucosa from Helicobacter-induced inflammation, but allows persistent Helicobacter colonization.

Automated summary

In Helicobacter-induced gastritis, PD-L1 may play a role in regulating immune responses. Gastric classical DCs express significantly higher levels of PD-L1 compared to other immune cells. Furthermore, PD-L1-expressing DCs co-localize with T cells and show a positive correlation with H pylori infection.