Protective Effects of PD-L1–Overexpressing MSCs and Their Derived Extracellular Vesicles in Type 1 Diabetes

Type 1 diabetes (T1D) is an autoimmune disorder characterized by T cell-mediated destruction of pancreatic β-cells that leads to lifelong dependence on insulin therapy. This study explores the therapeutic potential and mechanistic insights of human mesenchymal stromal/stem cells (MSCs) engineered to overexpress programmed death ligand-1 (PD-L1) (PD-L1-MSCs), as well as their extracellular vesicles (PEVs), in modulating immune responses and preserving pancreatic islet survival and function in a nonobese diabetic mouse model. PD-L1-MSCs were generated via lentiviral transduction and fully characterized before functional testing. In vitro, PD-L1-MSCs and PEVs demonstrated enhanced immunosuppressive capability with reduced T-cell proliferation, increased regulatory T cells (Tregs), and improved islet survival compared with corresponding controls. These effects were attenuated by blocking PD-L1 signaling with anti–PD-L1 antibodies. In vivo, a single infusion of PD-L1-MSCs or PEVs significantly delayed the onset of diabetes, lowered blood glucose levels, and reduced immune cell infiltration into pancreatic islets. Treated mice showed increased numbers of Tregs and exhausted CD8+ T cells. These findings suggest that PD-L1-MSCs and PEVs hold promise as immunomodulatory therapies for T1D, likely through PD-L1 expression, promotion of immune tolerance via Treg induction, and suppression of pathogenic CD8+ T cells. Article Highlights This study was conducted to address the urgent need for novel therapies for type 1 diabetes. We investigated whether programmed death-ligand 1 (PD-L1)–overexpressing mesenchymal stromal/stem cells (PD-L1-MSCs) and their extracellular vesicles (PEVs) can modulate immune responses and protect pancreatic islets, and whether these effects depend on PD-L1 signaling. Our results demonstrate that both PD-L1-MSCs and PEVs suppress T-cell activity, enhance regulatory T-cell populations, delay the onset of diabetes, and reduce immune cell infiltration in pancreatic islets. These findings suggest that PD-L1-MSCs and PEVs represent promising therapeutic strategies for type 1 diabetes by promoting immune tolerance and preserving β-cell function.