Mechanisms of PDL-1 mediated regulation of autoimmune diabetes
Mechanisms of PDL-1 mediated regulation of autoimmune diabetes
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DOI：
10.1016/j.clim.2007.05.013
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发表时间：
2007-10-01
影响因子：
8.6
通讯作者：
Sayegh, Mohamed H.
中科院分区：
文献类型：
--
作者：
Guleria, Indira;Bupp, Melanie Gubbels;Sayegh, Mohamed H.
PD-1-PDL1通路在调节自身免疫性糖尿病中起关键作用，因为PD-1或PDL1的阻断或缺乏会导致NOD小鼠疾病加速。我们通过对NOD背景下多种基因缺陷小鼠的研究，探讨了参与这些自身免疫反应调节的细胞机制。阻断抗pdl1抗体对CD4+ T细胞缺陷、CD8+ T细胞缺陷和B细胞缺陷小鼠的治疗表明，pdl1介导的自身反应性CD4+和CD8+ T细胞的调节对糖尿病的发展至关重要。利用BDC2.5和4.1 (CD4+) TCR转基因小鼠和8.3 (CD8+) TCR转基因小鼠的淋巴细胞进行过继转移研究证实了这一概念；研究表明，在体内PDL1阻断后，CD4+和CD8+ T细胞的增殖均增加。此外，我们观察到抗pdl1介导的加速依赖于疾病早期发生在胰腺淋巴结的事件，但在疾病晚期与胰腺淋巴结无关。这些数据提供了强有力的证据，证明PDL1通过限制CD4+和CD8+自身反应性T细胞的扩张来调节自身免疫性糖尿病，并确定了PDL1介导的1型糖尿病调节的时间和位置。(c) 2007爱思唯尔公司版权所有。
The PD-1-PDL1 pathway plays a critical rote in regulating autoimmune diabetes as blockade or deficiency of PD-1 or PDL1 results in accelerated disease in NOD mice. We explored I the cellular mechanisms involved in the regulation of these autoimmune responses by investigations involving various gene-deficient mice on the NOD background. Administration of blocking anti-PDL1 antibody to CD4+ T cell-deficient, CD8+ T cell-deficient and B cell-deficient mice demonstrated that PDL1-mediated regulation of autoreactive CD4+ and CD8+ T cells is critical for diabetes development. This concept was confirmed by adoptive transfer studies utilizing lymphocytes from BDC2.5 and 4.1 (CD4+) TCR transgenic mice and 8.3 (CD8+) TCR transgenic mice; efforts showing increased proliferation of both CD4+ and CD8+ T cells following PDL1 blockade in vivo. Furthermore, we observed that anti-PDL1-mediated acceleration is dependent upon events occurring in the pancreatic lymph nodes during early disease stages, but becomes independent of the pancreatic lymph nodes during later disease stages. These data provide strong evidence that PDL1 regulates autoimmune diabetes by limiting the expansion of CD4+ and CD8+ autoreactive T cells, and define the timing and locate of PDL1-mediated regulation of type 1 diabetes. (c) 2007 Elsevier Inc. All rights reserved.