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Stem cell–derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes
Mohammad Haque, … , Jin-Ming Yang, Jianxun Song
Mohammad Haque, … , Jin-Ming Yang, Jianxun Song
Published February 19, 2019
Citation Information: JCI Insight. 2019;4(7):e126471. https://doi.org/10.1172/jci.insight.126471.
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Research Article Immunology

Stem cell–derived tissue-associated regulatory T cells suppress the activity of pathogenic cells in autoimmune diabetes

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Abstract

The autoantigen-specific Tregs from pluripotent stem cells (PSCs), i.e., PSC-Tregs, have the ability to suppress autoimmunity. PSC-Tregs can be programmed to be tissue associated and to infiltrate into local inflamed tissues to suppress autoimmune responses after adoptive transfer. Nevertheless, the mechanisms by which the autoantigen-specific PSC-Tregs suppress the autoimmune response remain to be fully elucidated. In this study, we generated functional autoantigen-specific Tregs from the induced PSC (iPSCs), i.e., iPSC-Tregs, and investigated the underlying mechanisms of autoimmunity suppression by these Tregs in a type 1 diabetes (T1D) murine model. A double-Tg mouse model of T1D was established in F1 mice, in which the first generation of RIP-mOVA Tg mice that were crossed with OT-I T cell receptor (TCR) Tg mice was challenged with vaccinia viruses expressing OVA (VACV-OVA). We show that adoptive transfer of OVA-specific iPSC-Tregs greatly suppressed autoimmunity in the animal model and prevented the insulin-secreting pancreatic β cells from destruction. Further, we demonstrate that the adoptive transfer significantly reduced the expression of ICAM-1 in the diabetic pancreas and inhibited the migration of pathogenic CD8+ T cells and the production of the proinflammatory IFN-γ in the pancreas. These results indicate that the stem cell–derived tissue-associated Tregs can robustly accumulate in the diabetic pancreas, and, through downregulating the expression of ICAM-1 in the local inflamed tissues and inhibiting the production of proinflammatory cytokine IFN-γ, suppress the migration and activity of the pathogenic immune cells that cause T1D.

Authors

Mohammad Haque, Fengyang Lei, Xiaofang Xiong, Jugal Kishore Das, Xingcong Ren, Deyu Fang, Shahram Salek-Ardakani, Jin-Ming Yang, Jianxun Song

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Figure 4

Prevention of destruction of pancreatic β cells and suppression of autoimmune diabetes by autoantigen-specific iPSCs-Tregs.

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Prevention of destruction of pancreatic β cells and suppression of autoi...
Control cells or pre-iPSC-Tregs were adoptively transferred into diabetic mice, as described in Figure 3. (A) Blood sugar measurement at various weeks. Data shown are representative of 5 mice per group in 3 independent experiments. **P < 0.001; ***P < 0.0001, 2-way ANOVA analysis. (B) Immunofluorescence detection of pathogenic immune cells. Mice were sacrificed and pancreases were isolated for immunohistochemistry staining with CD8+ T cells (original magnification, ×200). Scale bar: 20.1 μm. Data are representative of 5 mice per group in 3 independent experiments. (C) Flow cytometric analysis of pathogenic immune cells. Pancreatic lymph nodes (LNs) were isolated, and single-cell suspensions were prepared for OVA-specific CD8+ TCRVβ5+ staining and analyzed by flow cytometry. Data shown are representative of 3 identical experiments (P < 0.001, Student’s 1-tailed t test). (D) Percentage of incidence of diabetes at week 22. Data shown are representative of 5 mice per group in 3 independent experiments. The values represent mean ± SD. **P < 0.001; ***P < 0.001, 1-way ANOVA analysis. (E) Representative photomicrographs (H&E staining) of the islet inflammation (original magnification, ×200). Scale bar: 20.4 μm. Cellular infiltrations (arrow) are indicated. Data are representative of 5 mice per group in 3 independent experiments. (F) Islet count from sections of 5 individual pancreases in each group. Data are represented as the mean ± SD of 3 independent experiments (***P < 0.001, 1-way ANOVA analysis). (G) Representative photomicrographs (immunofluorescence staining) of islet destruction (original magnification, ×200). Scale bar: 20.1 μm. Insulin-producing cells (arrow) are indicated. Data are representative of 5 mice per group in 3 independent experiments.

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