Low dose streptozotocin-induced diabetes in rat insulin promoter-mCD80-transgenic mice is T cell autoantigen-specific and CD28 dependent
Low dose streptozotocin-induced diabetes in rat insulin promoter-mCD80-transgenic mice is T cell autoantigen-specific and CD28 dependent
复制标题
DOI：
10.4049/jimmunol.166.4.2531
复制
发表时间：
2001-02-15
影响因子：
4.4
通讯作者：
Harlan, DM
中科院分区：
文献类型：
--
作者：
Pechhold, K;Patterson, NB;Harlan, DM
尽管在大鼠胰岛素-1启动子下在其胰腺β细胞上表达鼠B7-1（mCD 80）的转基因小鼠（RIPmCD 80（+）小鼠）很少发生自发性β细胞破坏和糖尿病，但我们以前曾报道过在RIP-mCD 80（+）小鼠中多次低剂量注射β细胞毒素链脲佐菌素（MLDS）后转基因依赖性诱导严重胰岛炎和致死性糖尿病。在这里，我们使用RIP-mCD 80（+）小鼠进一步表征了这种MLDS诱导的糖尿病模型，现在证明疾病严重依赖于通过CD 28的T细胞信号传导。因此，尽管初始RTP-mCD 80（+）和非转基因同窝小鼠具有相当的总β细胞质量，并且在MLDS诱导后小鼠立即显示出相似程度的胰岛炎和β细胞质量减少，但只有转基因小鼠继续破坏其P细胞并发展为胰岛素依赖性糖尿病。引人注目的是，由于白细胞浸润其胰岛的消除，MLDS诱导的糖尿病在CD 28缺陷小鼠（RIP-mCD 80（+）CD 28（-/-））中被完全预防。我们通过证明MLDS诱导的淋巴细胞胰岛浸润物含有大量自身抗原特异性、分泌IPN-γ的CD 8（+）T细胞，进一步表征了RIP-mCD 80（+）小鼠中MLDS诱导的糖尿病。我们得出结论，MLDS诱导的RIP-mCD 80（+）小鼠中的P细胞破坏和随后的胰岛素依赖型糖尿病是T细胞介导的，因为它涉及炎症胰岛中自身靶分子的Ag特异性识别（信号1）和CD 28共刺激依赖性（信号2）。免疫学杂志，2001，166：2531-2539.
Although transgenic mice expressing murine B7-1 (mCD80) on their pancreatic beta cells under the rat insulin-1 promoter (RIPmCD80(+) mice) rarely develop spontaneous beta cell destruction and diabetes, we have previously reported the transgene-dependent induction of profound insulitis and lethal diabetes following multiple low dose injections of the beta cell toxin streptozotocin (MLDS) in RIP-mCD80(+) mice. Here, we have further characterized this MLDS-induced diabetes model using the RIP-mCD80(+) mice and now demonstrate that disease is critically dependent on T cell signaling via CD28. Thus, although naive RTP-mCD80(+) and nontransgenic littermates have comparable gross beta cell mass, and immediately following MLDS induction the mice display similar degrees of insulitis and decrements in the beta cell mass, only transgenic mice continued to destroy their P cells and develop insulin-dependent diabetes mellitus. Strikingly, MLDS-induced diabetes was completely prevented in CD28-deficient mice (RIP-mCD80(+)CD28(-/-)) due to abrogation of leukocytes infiltrating their pancreatic islets. We further characterized MLDS-induced diabetes in the RIP-mCD80(+) mice by demonstrating that the MLDS-induced lymphocytic islet infiltrate contained a substantial frequency of autoantigen-specific, IPN-gamma -secreting, CD8(+) T cells. We conclude that MLDS-induced P cell, destruction and subsequent insulin-dependent diabetes mellitus in RIP-mCD80(+) mice is T cell-mediated as it involves both Ag-specific recognition of self-target molecules in the inflamed pancreatic islet (signal 1) and is CD28 costimulation dependent (signal 2). The Journal of Immunology, 2001, 166: 2531-2539.