Cytotoxic T-Cells From T-Cell Receptor Transgenic NOD8.3 Mice Destroy β-Cells via the Perforin and Fas Pathways

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 9; pp. 2412 - 2418
• Main Authors: DUDEK, Nadine L, THOMAS, Helen E, KAY, Thomas W. H, MARIANA, Lina, SUTHERLAND, Robyn M, ALLISON, Janette, ESTELLA, Eugene, ANGSTETRA, Eveline, TRAPANI, Joseph A, SANTAMARIA, Pere, LEW, Andrew M
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-09-2006
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Animals; Antigen receptors, T cell; Biological and medical sciences; CD8-Positive T-Lymphocytes - physiology; Diabetes Mellitus, Type 1 - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; fas Receptor - physiology; Fas-Associated Death Domain Protein; Genetic aspects; Glucose-6-Phosphatase - physiology; Insulin-Secreting Cells - cytology; Islets of Langerhans Transplantation - physiology; Medical sciences; Membrane Glycoproteins - physiology; Mice; Mice, Inbred NOD; Mice, Transgenic; Pancreatic beta cells; Perforin; Pore Forming Cytotoxic Proteins; Proteins - physiology; Receptors; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins - physiology; T cells; T-Lymphocytes, Cytotoxic - physiology; Type 1 diabetes; Endocrinopathy; T cell receptor; Diabetes mellitus; Langerhans islet; Rodentia; Transgenic animal; Vertebrata; Mammalia; Mouse; T-Lymphocyte; Fas Antigen; β Cell; Endocrine pancreas
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-0109

Cytotoxic T-Cells From T-Cell Receptor Transgenic NOD8.3 Mice Destroy β-Cells via the Perforin and Fas Pathways
Nadine L. Dudek 1 ,
Helen E. Thomas 1 ,
Lina Mariana 1 ,
Robyn M. Sutherland 2 ,
Janette Allison 1 ,
Eugene Estella 1 ,
Eveline Angstetra 1 ,
Joseph A. Trapani 3 ,
Pere Santamaria 4 ,
Andrew M. Lew 2 and
Thomas W.H. Kay 1 5
1 St. Vincent’s Institute, Fitzroy, Victoria, Australia
2 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
3 Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
4 Julia McFarlane Diabetes Research Center and Department of Microbiology and Infectious Disease, University of Calgary Faculty
of Medicine, Calgary, Alberta, Canada
5 The University of Melbourne Department of Medicine, St. Vincent’s Hospital, Fitzroy, Victoria, Australia
Address correspondence and reprint requests to Professor Thomas W.H. Kay, St. Vincent’s Institute, 41 Victoria Parade, Fitzroy,
Victoria 3065, Australia. E-mail: tkay{at}svi.edu.au
Abstract
Cytotoxic T-cells are the major mediators of β-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 β-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 β-cell killing only when perforin is missing. Consistent with this theory,
transgenic NOD8.3 mice with β-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 β-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 β-cells and the surprising blockade of NOD8.3 T-cell–mediated β-cell death by SOCS-1 overexpression
may be due in part to reduced target cell recognition.
CTL, cytotoxic T-cell
dn, dominant-negative
FasL, Fas ligand
FADD, Fas-associated death domain
IGRP, islet-specific glucose 6-phosphatase catalytic subunit–related protein
IFN, interferon
MHC, major histocompatibility complex
PLN, pancreatic lymph node
RIP, rat insulin promotor
SOCS-1, suppressor of cytokine signaling-1
TCR, T-cell receptor
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted June 8, 2006.
Received January 24, 2006.
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