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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 3

Accumulation of autoantigen-specific iPSC-Tregs in the pancreases of diabetic mice following adoptive transfer.

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Accumulation of autoantigen-specific iPSC-Tregs in the pancreases of dia...
B6-mOVA Tg × OT-I TCR double-Tg mice were immunized with VACV-OVA. At week 10, control cells or OVA- or SM1-specific pre-iPSC-Tregs were transferred into diabetic mice. Before or after the cell transfer, mice were sacrificed and their pancreases were isolated for analysis of CD4 and FoxP3. (A) Immunohistology at week 13 (original magnification, ×200). Scale bar: 20.1 μm. (B) Flow cytometric analysis at week 10 (before the cell transfer), 13, and 16. Data are representative of 5 mice per group in 3 independent experiments.

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