Comparing the relative role of perforin/granzyme versus Fas/Fas ligand cytotoxic pathways in CD8+ T cell-mediated insulin-dependent diabetes mellitus

Huub T.C. Kreuwel, David J. Morgan, Troy Krahl, Alice Ko, Nora Sarvetnick, Linda A. Sherman

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

CD8+ cytotoxic T cells play a critical role in initiating insulin- dependent diabetes mellitus. The relative contribution of each of the major cytotoxic pathways, perforin/granzyme and Fas/Fas ligand (FasL), in the induction of autoimmune diabetes remains controversial. To evaluate the role of each lytic pathway in β cell lysis and induction of diabetes, we have used a transgenic mouse model in which β cells expressing the influenza virus hemagglutinin (HA) are destroyed by HA-specific CD8+ T cells from clone-4 TCR-transgenic mice. Upon adoptive transfer of CD8+ T cells from perforin-deficient clone-4 TCR mice, there was a 30-fold increase in the number of T cells required to induce diabetes. In contrast, elimination of the Fas/FasL pathway of cytotoxicity had little consequence. When both pathways of cytolysis were eliminated, mice did not become diabetic. Using a model of spontaneous diabetes, which occurs in double transgenic neonates that express both clone-4 TCR and Ins-HA transgenes, mice deficient in either the perforin or FasL/Fas lytic pathway become diabetic soon after birth. This indicates that, in the neonate, large numbers of autoreactive CD8+ T cells can lead to destruction of islet β cells by either pathway.

Original languageEnglish (US)
Pages (from-to)4335-4341
Number of pages7
JournalJournal of Immunology
Volume163
Issue number8
StatePublished - 1999

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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