title: Comparing the relative role of perforin/granzyme versus Fas/Fas ligand cytotoxic pathways in CD8+ T cell-mediated insulin-dependent diabetes mellitus.
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 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.
authors.affiliation: Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: H T
authors.initials: HT
authors.lastname: Kreuwel
authors.forename: D J
authors.initials: DJ
authors.lastname: Morgan
authors.forename: T
authors.initials: T
authors.lastname: Krahl
authors.forename: A
authors.initials: A
authors.lastname: Ko
authors.forename: N
authors.initials: N
authors.lastname: Sarvetnick
authors.forename: L A
authors.initials: LA
authors.lastname: Sherman
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000831:Animals, Newborn / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053222:Fas Ligand Protein; D053804:Granzymes; D007150:Immunohistochemistry; D007515:Islets of Langerhans / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011828:Radiation Chimera / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012697:Serine Endopeptidases / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000276:immunology / Q000502:physiology*
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011948:Receptors, Antigen, T-Cell; D019014:fas Receptor; D054353:Perforin; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases