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 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 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.
|Number of pages||25|
|Journal||Cellular and Molecular Gastroenterology and Hepatology|
|Publication status||Published - 2021 Jan|
Bibliographical noteFunding Information:
Funding This research was supported by NRF-2016M3A9D5A01952416, 2016M3A9D5A01952413, 2018R1A2B6003393, and 2015M3A9B6029138, and by the National Research Foundation of the Korean government.
© 2021 The Authors
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