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.
Publication types
-
Comparative Study
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adoptive Transfer
-
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
-
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
-
fas Receptor / immunology
-
fas Receptor / physiology*
Substances
-
Fas Ligand Protein
-
Fasl protein, mouse
-
Ligands
-
Membrane Glycoproteins
-
Pore Forming Cytotoxic Proteins
-
Receptors, Antigen, T-Cell
-
fas Receptor
-
Perforin
-
Granzymes
-
Gzmb protein, mouse
-
Serine Endopeptidases