Programmed Death Ligand 1-Expressing Classical Dendritic Cells MitigateHelicobacter-Induced Gastritis

• Published in: Cellular and molecular gastroenterology and hepatology 2021, Vol.12 (2), p.715-739
• Main Authors: Go, Du-Min, Lee, Seung Hyun, Lee, Su-Hyung, Woo, Sang-Ho, Kim, Kibyeong, Kim, Kyeongdae, Park, Kyu Seong, Park, Jong-Hwan, Ha, Sang-Jun, Kim, Woo Ho, Choi, Jae-Hoon, Kim, Dae-Yong
• Format: Article
• Language: English
• Subjects: Animals; Antibodies - pharmacology; B7-H1 Antigen - metabolism; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Bone Marrow Transplantation; CD11 Antigens - metabolism; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; Dendritic Cells - metabolism; fms-Like Tyrosine Kinase 3 - deficiency; fms-Like Tyrosine Kinase 3 - metabolism; Gastric Inflammation; Gastric Mucosa - drug effects; Gastric Mucosa - pathology; Gastritis - metabolism; Gastritis - microbiology; Gastritis - pathology; Helicobacter Infections - microbiology; Helicobacter Infections - pathology; Helicobacter pylori - drug effects; Helicobacter pylori - physiology; Immune Regulation; Inflammation - pathology; Male; Metaplasia; Mice; Mice, Inbred C57BL; Mucosal Metaplasia; T Cell; T-Lymphocytes - immunology
• ISSN: 2352-345X; 2352-345X
• DOI: 10.1016/j.jcmgh.2021.04.007

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. 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. 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. 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. [Display omitted]