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

Du Min Go, Seung Hyun Lee, Su Hyung Lee, Sang Ho Woo, Kibyeong Kim, Kyeongdae Kim, Kyu Seong Park, Jong Hwan Park, Sang Jun Ha, Woo Ho Kim, Jae Hoon Choi, Dae Yong Kim

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)715-739
Number of pages25
JournalCellular and Molecular Gastroenterology and Hepatology
Volume12
Issue number2
DOIs
Publication statusPublished - 2021 Jan

Bibliographical note

Funding Information:
Funding This research was supported by NRF-2016M3A9D5A01952416, 2016M3A9D5A01952413, 2018R1A2B6003393, and 2015M3A9B6029138, and by the National Research Foundation of the Korean government.

Publisher Copyright:
© 2021 The Authors

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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