Schlafen 4–expressing myeloid-derived suppressor cells are induced during murine gastric metaplasia
Lin Ding, … , Ramon Ocadiz-Ruiz, Juanita L. Merchant
Lin Ding, … , Ramon Ocadiz-Ruiz, Juanita L. Merchant
Published July 18, 2016
Citation Information: J Clin Invest. 2016;126(8):2867-2880. https://doi.org/10.1172/JCI82529.
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Research Article Oncology

Schlafen 4–expressing myeloid-derived suppressor cells are induced during murine gastric metaplasia

Abstract

Chronic Helicobacter pylori infection triggers neoplastic transformation of the gastric mucosa in a small subset of patients, but the risk factors that induce progression to gastric metaplasia have not been identified. Prior to cancer development, the oxyntic gastric glands atrophy and are replaced by metaplastic cells in response to chronic gastritis. Previously, we identified schlafen 4 (Slfn4) as a GLI1 target gene and myeloid differentiation factor that correlates with spasmolytic polypeptide-expressing metaplasia (SPEM) in mice. Here, we tested the hypothesis that migration of SLFN4-expressing cells from the bone marrow to peripheral organs predicts preneoplastic changes in the gastric microenvironment. Lineage tracing in Helicobacter-infected Slfn4 reporter mice revealed that SLFN4+ cells migrated to the stomach, where they exhibited myeloid-derived suppressor cell (MDSC) markers and acquired the ability to inhibit T cell proliferation. SLFN4+ MDSCs were not observed in infected GLI1-deficient mice. Overexpression of sonic hedgehog ligand (SHH) in infected WT mice accelerated the appearance of SLFN4+ MDSCs in the gastric corpus. Similarly, in the stomachs of H. pylori–infected patients, the human SLFN4 ortholog SLFN12L colocalized to cells that expressed MDSC surface markers CD15+CD33+HLA-DRlo. Together, these results indicate that SLFN4 marks a GLI1-dependent population of MDSCs that predict a shift in the gastric mucosa to a metaplastic phenotype.

Authors

Lin Ding, Michael M. Hayes, Amanda Photenhauer, Kathryn A. Eaton, Qian Li, Ramon Ocadiz-Ruiz, Juanita L. Merchant

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Figure 4

SLFN4+ cells from gastric corpus suppress T cell proliferation.

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SLFN4+ cells from gastric corpus suppress T cell proliferation. (A) SLFN...
(A) SLFN4+ cells from bone marrow, spleen, and corpus were analyzed for Ly6G, Ly6C, and iNOS expression. Gated SLFN4+iNOS+ cells from the corpus were further analyzed for arginase I (ARG1). Median percentage (interquartile range) for each gated subpopulation shown in red for n = 4 mice per tissue. (B) Representative images from n = 4 mouse stomachs of SLFN4-tdT+ cells (red) colocalized with ARG1 (green) or iNOS (green). Scale bars: 20 μm. Asterisks indicate colocalization. (C) SLFN4+ cells were sorted from the indicated tissues of 3 pooled 4-month-infected infected pCMV-Shh mice and then cocultured with naive splenic T cells prestained with the CFSE dye. T cell proliferation was initiated with anti-CD3/CD28 microbeads cultured with or without SLFN4+ cells for 72 hours, and CFSE+ T cells were quantified by flow cytometry. The median percentage of proliferating T cells is shown in the representative histograms (nos. 1–6) plotted for n = 5 experiments in the scatter graph. Tregs (CD4+CD25+) from spleen were used as the positive control. Kruskal-Wallis ANOVA with Dunn’s test of multiple comparisons was performed. *P < 0.05.