Pharmacological inhibition of perforin dampens CD8+ T cell-mediated beta cell destruction in autoimmune diabetes in mice
- Author(s)
- Trivedi, PM; Catterall, T; Sutton, VR; Moshovakis, V; Elkerbout, L; Akhlaghi, H; Spicer, JA; Boon, L; Kay, TWH; Trapani, JA; Thomas, HE;
- Journal Title
- Diabetologia
- Publication Type
- Online publication before print
- Abstract
- AIMS/HYPOTHESIS: CD8⁺ T cells are key mediators of beta cell destruction in type 1 diabetes, employing the perforin/granzyme and Fas/Fas ligand pathways. Evidence from our studies and others indicates that perforin plays a dominant role in CD8⁺ T cell mediated beta cell destruction in non-obese diabetic (NOD) mice. As perforin is indispensable for delivering pro-apoptotic granzymes into the cytosol of target cells, pharmacological inhibition of perforin may potentially protect beta cells against CD8(+) T cell cytotoxicity. Such a strategy will slow down beta cell loss and the progression to autoimmune diabetes. Small molecule perforin inhibitors recently becoming available provided an opportunity to test this hypothesis. METHODS: The new small molecule perforin inhibitor SN34960 was evaluated for its ability to protect the beta cells of non-obese diabetic mice upon attack by autoreactive cytotoxic T lymphocytes, both in vitro and in vivo. RESULTS: In vitro, perforin inhibitor SN34960 protected isolated pancreatic islets from CD8(+) T cell-mediated destruction (p<0.001). In vivo, a single dose of SN34960 reduced the death of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) peptide-loaded target cells by ~50% over 16 h compared with non-peptide-loaded control cells (p<0.05). Furthermore, prediabetic NOD mice treated with perforin inhibitor for 7 days had a reduced incidence of diabetes when autoimmune attack was accelerated by anti-PDL1 blockade (91.2% vs 58.4%, p<0.05). Pharmacological perforin inhibition with SN34960 did not alter the activation or differentiation status of pathogenic cytotoxic T lymphocyte infiltrating the pancreas; instead, its mode of action is specifically to block the membrane-disruptive and pro-apoptotic effects of perforin following its secretion into the synaptic cleft. CONCLUSIONS/INTERPRETATION: Our results suggest that pharmacological perforin inhibition may represent a novel approach to protect beta cells from destruction by autoreactive CD8(+) T cells.
- Keywords
- Apoptosis; Autoimmunity; Beta cell; Cytotoxic T lymphocyte; Focused immunosuppressant drug; Granzyme; NOD mouse; Perforin; Type 1 diabetes
- Department(s)
- Laboratory Research
- Publisher's Version
- https://doi.org/10.1007/s00125-026-06773-8
- Open Access at Publisher's Site
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Creation Date: 2026-07-02 01:34:29
Last Modified: 2026-07-02 01:34:39