Cytotoxic T-cells from T-cell receptor transgenic NOD8.3 mice destroy beta-cells via the perforin and Fas pathways.
Cytotoxic T-cells are the major mediators of beta-cell destruction in type 1 diabetes, but the molecular mechanisms are not definitively established. We have examined the contribution of perforin and Fas ligand to beta-cell destruction using islet-specific CD8(+) T-cells from T-cell receptor transgenic NOD8.3 mice. NOD8.3 T-cells killed Fas-deficient islets in vitro and in vivo. Perforin-deficient NOD8.3 T-cells were able to destroy wild-type but not Fas-deficient islets in vitro. These results imply that NOD8.3 T-cells use both pathways and that Fas is required for beta-cell killing only when perforin is missing. Consistent with this theory, transgenic NOD8.3 mice with beta-cells that do not respond to Fas ligation were not protected from diabetes. We next investigated the mechanism of protection provided by overexpression of suppressor of cytokine signaling-1 (SOCS-1) in beta-cells of NOD8.3 mice. SOCS-1 islets remained intact when grafted into NOD8.3 mice and were less efficiently killed in vitro. However, addition of exogenous peptide rendered SOCS-1 islets susceptible to 8.3 T-cell-mediated lysis. Therefore, NOD8.3 T-cells use both perforin and Fas pathways to kill beta-cells and the surprising blockade of NOD8.3 T-cell-mediated beta-cell death by SOCS-1 overexpression may be due in part to reduced target cell recognition.
Dudek
Nadine L
NL
St. Vincent's Institute, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia.
Thomas
Helen E
HE
Mariana
Lina
L
Sutherland
Robyn M
RM
Allison
Janette
J
Estella
Eugene
E
Angstetra
Eveline
E
Trapani
Joseph A
JA
Santamaria
Pere
P
Lew
Andrew M
AM
Kay
Thomas W H
TW
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D053200:Fas-Associated Death Domain Protein; D005952:Glucose-6-Phosphatase / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000166:cytology*; D016381:Islets of Langerhans Transplantation / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019014:fas Receptor; D054353:Perforin; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse