Journal article

Perforin facilitates beta cell killing and regulates autoreactive CD8( ) T-cell responses to antigen in mouse models of type 1 diabetes

Prerak Trivedi, Kate L Graham, Balasubramaninan Krishnamurthy, Stacey Fynch, Robyn M Slattery, Thomas Wh Kay, Helen E Thomas



In type 1 diabetes, cytotoxic CD8(+) T lymphocytes (CTLs) directly interact with pancreatic beta cells through major histocompatibility complex class I. An immune synapse facilitates delivery of cytotoxic granules, comprised mainly of granzymes and perforin. Perforin deficiency protects the majority of non-obese diabetic (NOD) mice from autoimmune diabetes. Intriguingly perforin deficiency does not prevent diabetes in CD8(+) T-cell receptor transgenic NOD8.3 mice. We therefore investigated the importance of perforin-dependent killing via CTL-beta cell contact in autoimmune diabetes. Perforin-deficient CTL from NOD mice or from NOD8.3 mice were significantly less efficient at adoptive transfe..

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Awarded by National Health and Medical Research Council of Australia (NHMRC)

Funding Acknowledgements

We thank Dr P Santamaria (University of Calgary) for NOD8.3 mice, L Elkerbout, S Thorburn, E Tanuwidjaya, E Duff (St Vincent's Institute) for technical support, genotyping and animal husbandry and Dr M Jenkins (Peter MacCallum Cancer Centre) for critical reading. This work was funded by a National Health and Medical Research Council of Australia (NHMRC) Program grant (APP1037321) and fellowships from the NHMRC (HET) and JDRF (BK). The St Vincent's Institute receives support from the Operational Infrastructure Support Scheme of the Government of Victoria.