Angstetra Eveline, Graham Kate L, Emmett Sarah, Dudek Nadine L, Darwiche Rima, Ayala-Perez Rochelle, Allison Janette, Santamaria Pere, Kay Thomas W H, Thomas Helen E
St Vincent's Institute, Fitzroy, Melbourne, Victoria, Australia.
Immunol Cell Biol. 2009 Feb;87(2):178-85. doi: 10.1038/icb.2008.81. Epub 2008 Nov 18.
CD4(+) T cells can actively kill beta-cells in type I diabetes as well as help CD8(+) T cells become cytolytic. Cytokines have the potential to kill beta-cells, or upregulate Fas on beta-cells, and increase their susceptibility to FasL. We investigated the direct effects of cytokines on beta-cells in perforin-deficient non-obese diabetic (NOD) mice and NOD4.1 TCR transgenic mice, two models in which CD8(+) T cells play a less dominant role. Inhibiting the effects of cytokines by the overexpression of suppressor of cytokine signalling-1 (SOCS1) in beta-cells did not reduce diabetes or insulitis in perforin-deficient NOD, NOD4.1 or interleukin (IL)-1 receptor-deficient NOD4.1 mice. SOCS1 overexpression prevented Fas upregulation on NOD4.1 beta-cells, but did not prevent islet destruction because SOCS1 transgenic islets were killed when grafted into NOD4.1.scid mice. Likewise, Fas-deficient NOD.lpr islets were destroyed in NOD4.1 mice. Although blocking the effects of interferon (IFN)gamma on beta-cells did not affect diabetes in NOD4.1 mice, global deficiency of IFNgammaR2 reduced diabetes and insulitis, suggesting that IFNgamma is involved in CD4(+) T-cell activation or migration. Our data show that beta-cells under attack by CD4(+) T cells are not destroyed by the effects of cytokines including IFNgamma and IL-1 or Fas-dependent cytotoxicity.
CD4(+) T细胞在I型糖尿病中可主动杀伤β细胞，还能帮助CD8(+) T细胞成为细胞溶解细胞。细胞因子有可能杀伤β细胞，或上调β细胞上的Fas，并增加其对FasL的敏感性。我们研究了细胞因子对穿孔素缺陷的非肥胖糖尿病（NOD）小鼠和NOD4.1 TCR转基因小鼠β细胞的直接影响，在这两种模型中CD8(+) T细胞发挥的作用不那么突出。通过在β细胞中过表达细胞因子信号抑制因子-1（SOCS1）来抑制细胞因子的作用，并没有降低穿孔素缺陷的NOD、NOD4.1或白细胞介素（IL）-1受体缺陷的NOD4.1小鼠的糖尿病或胰岛炎。SOCS1过表达可防止NOD4.1 β细胞上的Fas上调，但不能防止胰岛破坏，因为当将SOCS1转基因胰岛移植到NOD4.1.scid小鼠体内时，这些胰岛会被杀死。同样，Fas缺陷的NOD.lpr胰岛在NOD4.1小鼠中也会被破坏。虽然阻断干扰素（IFN）γ对β细胞的作用不会影响NOD4.1小鼠的糖尿病，但IFNγR2的整体缺陷可减轻糖尿病和胰岛炎，这表明IFNγ参与了CD4(+) T细胞的激活或迁移。我们的数据表明，受到CD4(+) T细胞攻击的β细胞不会被包括IFNγ和IL-1在内的细胞因子的作用或Fas依赖性细胞毒性所破坏。
