Cytotoxic T-Cells from T-Cell receptor transgenic NOD8.3 mice destroy β-cells via the perforin and fas pathways
Cytotoxic T-Cells from T-Cell receptor transgenic NOD8.3 mice destroy β-cells via the perforin and fas pathways
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DOI：
10.2337/db06-0109
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发表时间：
2006-09-01
期刊：
影响因子：
7.7
通讯作者：
Kay, Thomas W. H.
中科院分区：
文献类型：
--
作者：
Dudek, Nadine L.;Thomas, Helen E.;Kay, Thomas W. H.
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.
