Regulation of Helicobacter-induced gastritis by programmed death ligand 1-expressing classical dendritic cells

ABSTRACT BACKGROUND & AIMS Helicobacter pylori has been reported to modulate local immune responses in order 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 Helicobacter 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 PD-L1 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 pylori-infected dendritic cell (DC)-deficient mouse models including Flt3–/–, Zbtb46-DTR, and BDCA2-DTR mice were analyzed for pathological changes and colonization levels. Finally, the location of PD-L1-expressing DCs and the correlation with Helicobacter 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 (cDCs) 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 humans. Helicobacter felis or pylori-infected Flt3–/– or cDC-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 are co-localized with T cells and showed positive correlation with Helicobacter 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.