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      Perforin and Fas induced by IFNgamma and TNFalpha mediate beta cell death by OT-I CTL.

      International Immunology
      Animals, Antibodies, Monoclonal, immunology, pharmacology, Antigens, CD95, Autoantibodies, Carrier Proteins, Cell Death, drug effects, Diabetes Mellitus, Type 1, Fas Ligand Protein, Genes, MHC Class I, Insulin-Secreting Cells, Interferon-gamma, Membrane Glycoproteins, deficiency, Mice, Mice, Transgenic, Peptides, Perforin, Pore Forming Cytotoxic Proteins, Receptors, Interferon, Repressor Proteins, Signal Transduction, genetics, Suppressor of Cytokine Signaling Proteins, T-Lymphocytes, Cytotoxic, Tumor Necrosis Factor-alpha, Tumor Necrosis Factors, Up-Regulation

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          Abstract

          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-TNFalpha) antibody or by blocking IFNgamma responsiveness through expressing a dominant negative IFNgamma receptor. Perforin-deficient CTL produced IFNgamma and TNFalpha that was shown to directly induce islet Fas expression during the assays. This suggests that Fas-deficiency, SOCS-1 overexpression and blockade of IFNgamma and TNFalpha 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 IFNgamma and TNFalpha.

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