International Immunology Advance Access originally published online on March 30, 2006
International Immunology 2006 18(6):837-846; doi:10.1093/intimm/dxl020
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Perforin and Fas induced by IFN
and TNF
mediate beta cell death by OT-I CTL
1 St Vincent's Institute, Fitzroy, Melbourne, Australia
2 Cancer Immunology Program, Research Division, Peter MacCallum Cancer Centre, East Melbourne, Australia
Correspondence to: T. W. H. Kay; E-mail: tkay{at}svi.edu.au
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
) 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.
Keywords: apoptosis, autoimmunity, cytotoxic T cells, diabetes, ovalbumin
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