Comparing the Relative Role of Perforin/Granzyme Versus Fas/Fas Ligand Cytotoxic Pathways in CD8+ T Cell-Mediated Insulin-Dependent Diabetes Mellitus

• Published in: The Journal of immunology (1950) Vol. 163; no. 8; pp. 4335 - 4341
• Main Authors: Kreuwel, Huub T. C, Morgan, David J, Krahl, Troy, Ko, Alice, Sarvetnick, Nora, Sherman, Linda A
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-10-1999
• Subjects: Adoptive Transfer; AIDS/HIV; Animals; Animals, Newborn - immunology; CD8-Positive T-Lymphocytes - enzymology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - transplantation; Clone Cells; Cytotoxicity, Immunologic; Diabetes Mellitus, Type 1 - enzymology; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - pathology; Fas Ligand Protein; fas Receptor - immunology; fas Receptor - physiology; Granzymes; Immunohistochemistry; Islets of Langerhans - chemistry; Islets of Langerhans - immunology; Islets of Langerhans - pathology; Ligands; Membrane Glycoproteins - immunology; Membrane Glycoproteins - physiology; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, Transgenic; Perforin; Pore Forming Cytotoxic Proteins; Radiation Chimera - immunology; Receptors, Antigen, T-Cell - immunology; Serine Endopeptidases - immunology; Serine Endopeptidases - physiology; Signal Transduction - immunology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.163.8.4335

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 beta cell lysis and induction of diabetes, we have used a transgenic mouse model in which beta 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 beta cells by either pathway.