International Immunology Advance Access published online on March 30, 2006
International Immunology, doi:10.1093/intimm/dxl020
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1 St Vincent's Institute, Fitzroy, Melbourne, Australia
* To whom correspondence should be addressed. Direct interaction between auto-reactive CTL and specific peptide-MHC class I complexes on pancreatic beta cells is critical in mediating beta cell destruction in type I diabetes. We used mice with genetic modifications in three major pathways used by CTL, perforin, Fas and pro-inflammatory cytokines to assess the relative contribution of these mechanisms to beta cell death. In vitro-activated ovalbumin (OVA)-specific CTL, from OT-I TCR-transgenic mice, specifically killed transgenic beta cells expressing OVA (from RIP-mOVA mice) in a 16-h cytotoxicity assay. Perforin-deficient CTL had a reduced ability to kill OVA-expressing islets in vitro (22.1 ± 3.8%) compared with wild-type CTL (71.4 ± 4.6%). Fas-deficient islets were only slightly protected from wild-type CTL but were completely protected from the residual killing observed with perforin-deficient CTL. Residual cytotoxicity in perforin-deficient CTL was also prevented by overexpression of SOCS-1, which blocks multiple cytokine signaling pathways. It was also prevented by pre-incubation with anti-tumor necrosis factor-alpha (anti-TNF
Received September 2, 2005
Accepted March 2, 2006
Article
Perforin and Fas induced by IFN
Mark D. McKenzie 1,
Nadine L. Dudek 1,
Lina Mariana 1,
Mark M. W. Chong 1,
Joseph A. Trapani 2,
Thomas W. H. Kay 1 *,
and
Helen E. Thomas 1
and TNF
mediate beta cell death by OT-I CTL
2 Cancer Immunology Program, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia
Thomas W. H. Kay, E-mail: tkay{at}svi.edu.au
Abstract 
) antibody or by blocking IFN
responsiveness through expressing a dominant negative IFN receptor. Perforin-deficient CTL produced IFN and TNF that was shown to directly induce islet Fas expression during the assays. This suggests that Fas-deficiency, SOCS-1 overexpression and blockade of IFN and TNF all protect beta cells from residual cytotoxicity of perforin-deficient CTL by blocking Fas upregulation. These findings indicate that wild-type CTL destroy antigen-expressing islets via a perforin-dependent mechanism. However, in the absence of perforin, the Fas/FasL pathway provides an alternative mechanism dependent on islet cell Fas upregulation by cytokines IFN and TNF.
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