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Journal article
Taming Autoimmunity: Alpha-1 Antitrypsin Overexpressing Mesenchymal Stem/Stromal Cells Promote Regulatory T Cell Crosstalk to Reverse Diabetes
Molecular therapy, Vol.online ahead of print(7)
03/31/2026
PMID: 41918165
Web of Science ID: WOS:001815823200001
Abstract
Mesenchymal stem/stromal cell (MSC) therapy holds promise as a therapeutic option in diabetes treatment. The anti-inflammatory and immunomodulatory activities are enhanced when MSCs are engineered to overexpress alpha-1 antitrypsin (AAT-MSCs). Because a single infusion of AAT-MSCs reversed new-onset diabetes in over 50% of the female nonobese diabetic (NOD) mice, we used singlecell RNA sequencing, flow cytometry, and functional analyses to characterize how AAT-MSCs modulate CD4+ and CD8+ T cells in pancreatic lymph nodes (PLNs) and islets. AAT-MSC treatment increased T regulatory cells (Tregs) and more effectively suppressed T cell proliferation when stimulated with anti-CD3/CD28 antibodies. Treated mice exhibited reduced T helper 1 (Th1) cells and CD8+ cytotoxic T cells. In vitro studies confirmed the capacity of AAT-MSCs to promote Treg expansion in both mouse and human cells, drive CD8+ T cells toward an exhausted phenotype, and enhance mouse and human islet cell survival. Cellchat analysis showed that AAT-MSC therapy strengthens intercellular communication, especially signals originating from Tregs toward other PLN and islet cell populations. These findings clarify how AAT-MSCs modulate immune response and support their potential clinical application for type 1 diabetes and other autoimmune or inflammatory conditions.
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Details
- Title
- Taming Autoimmunity
- Publication Details
- Molecular therapy, Vol.online ahead of print(7)
- Resource Type
- Journal article
- Publisher
- Cell Press
- Number of pages
- 19
- Grant note
- National Institutes of Health (R01): DK105183, DK120394, DK118529, DK126454, UH3DK136705 Department of Veterans Affairs (VA-ORD BLRD Merit): I01BX004536, I01CX002516 CNDD Genomics and Bioinformatics Core at Medical University of South Carolina (NIH): P20GM148302 Biorepository & Tissue Analysis Shared Resource, Hollings Cancer Center, Medical University of South Carolina: P30 CA138313
This study was supported in part by the National Institutes of Health (R01 DK105183, DK120394, DK118529, DK126454, and UH3DK136705) and the Department of Veterans Affairs (VA-ORD BLR&D Merit I01BX004536 and I01CX002516). S.S. and S.B. are supported by the CNDD Genomics and Bioinformatics Core at Medical University of South Carolina (NIH grant no. P20GM148302) and by the Biorepository & Tissue Analysis Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313). Some illustrations were created in BioRender (https://BioRender. com/elzcms9).
- Copyright
- © 2026 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
- Identifiers
- WOS:001815823200001; 99381814266406600
- Academic Unit
- Biology; Hal Marcus College of Science and Engineering
- Language
- English