Suppressor of cytokine signaling-1 overexpression protects pancreatic β cells from CD8+ T cell-mediated autoimmune destruction
Suppressor of cytokine signaling-1 overexpression protects pancreatic β cells from CD8+ T cell-mediated autoimmune destruction
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DOI：
10.4049/jimmunol.172.9.5714
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发表时间：
2004-05-01
影响因子：
4.4
通讯作者：
Thomas, HE
中科院分区：
文献类型：
--
作者：
Chong, MMW;Chen, Y;Thomas, HE
在 1 型糖尿病中，细胞因子对 β 细胞的作用可能通过直接细胞毒性、诱导 Fas 表达以及上调 I 类 MHC 和趋化因子表达以增加免疫识别来破坏 β 细胞。为了同时阻断 β 细胞对多种细胞因子的反应，我们过表达细胞因子信号传导抑制因子 1 (SOCS-1)。这完全阻止了 CD8(+) TCR 转基因非肥胖糖尿病 (NOD) 8.3 小鼠进展为糖尿病，而不影响胰腺浸润，并部分阻止了非转基因 NOD 小鼠的糖尿病。 SOCS-1 似乎至少部分通过抑制 TNF 和 IFN-γ 诱导的 β 细胞上的 Fas 表达来发挥保护作用。在糖尿病前期 NOD8.3 小鼠体内，β 细胞上的 Fas 表达上调，而这种表达被 SOCS-1 抑制。此外，IFN-γ 诱导的 I 类 MHC 上调以及 TNF 和 IFN-γ 诱导的 β 细胞 IL-15 表达均被 SOCS-1 抑制，这与体外抑制的 8.3 T 细胞增殖相关。尽管如此，体内 8.3 T 细胞启动似乎不受影响。因此，阻断β细胞对细胞因子的反应会损害CD8+T细胞的识别并阻断β细胞破坏的多种机制，但并不能阻止T细胞启动和募集到胰岛。我们的研究结果表明，增加 SOCS-1 的表达可能有助于阻断 CD8(+) T 细胞介导的 1 型糖尿病，以及更广泛地预防炎症性疾病中细胞因子依赖性组织破坏。
In type 1 diabetes, cytokine action on beta cells potentially contributes to beta cell destruction by direct cytotoxicity, inducing Fas expression, and up-regulating class I MHC and chemokine expression to increase immune recognition. To simultaneously block beta cell responsiveness to multiple cytokines, we overexpressed suppressor of cytokine signaling-1 (SOCS-1). This completely prevented progression to diabetes in CD8(+) TCR transgenic nonobese diabetic (NOD) 8.3 mice without affecting pancreas infiltration and partially prevented diabetes in nontransgenic NOD mice. SOCS-1 appeared to protect at least in part by inhibiting TNF- and IFN-gamma-induced Fas expression on beta cells. Fas expression was up-regulated on beta cells in vivo in prediabetic NOD8.3 mice, and this was inhibited by SOCS-1. Additionally, IFN-gamma-induced class I MHC up-regulation and TNF- and IFN-gamma-induced IL-15 expression by beta cells were inhibited by SOCS-1, which correlated with suppressed 8.3 T cell proliferation in vitro. Despite this, 8.3 T cell priming in vivo appeared unaffected. Therefore, blocking beta cell responses to cytokines impairs recognition by CD8(+) T cells and blocks multiple mechanisms of beta cell destruction, but does not prevent T cell priming and recruitment to the islets. Our findings suggest that increasing SOCS-1 expression may be useful as a strategy to block CD8(+) T cell-mediated type 1 diabetes as well as to more generally prevent cytokine-dependent tissue destruction in inflammatory diseases.