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B7-H1（PD-L1）/PD-1 共抑制缺陷通过胰岛素特异性的、鼠源 CD8 T 细胞触发胰岛β细胞破坏。

Deficiency in B7-H1 (PD-L1)/PD-1 coinhibition triggers pancreatic beta-cell destruction by insulin-specific, murine CD8 T-cells.

机构信息

Department of Internal Medicine I, University Hospital of Ulm, Ulm,Germany.

出版信息

Diabetes. 2010 Aug;59(8):1966-73. doi: 10.2337/db09-1135. Epub 2010 May 18.

DOI:10.2337/db09-1135
PMID:20484136
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2911076/
Abstract

OBJECTIVE

RIP-B7.1 mice expressing the costimulator molecule B7.1 (CD80) on pancreatic beta-cells are a well established model to characterize preproinsulin-specific CD8 T-cell responses and experimental autoimmune diabetes (EAD). Different immunization strategies could prime preproinsulin-specific CD8 T-cells in wild-type C57BL/6 (B6) mice, but did not induce diabetes. We tested whether altering the B7-H1 (PD-L1) coinhibition on pancreatic beta-cells can reveal a diabetogenic potential of preproinsulin-specific CD8 T-cells.

RESEARCH DESIGN AND METHODS

DNA-based immunization and adoptive T-cell transfers were used to characterize the induction of preproinsulin-specific CD8 T-cell responses and EAD in RIP-B7.1, B6, B7-H1(-/-), PD-1(-/-) or bone marrow chimeric mice.

RESULTS

Preproinsulin-specific CD8 T-cells primed in B6 mice revealed their diabetogenic potential after adoptive transfer into congenic RIP-B7.1 hosts. Furthermore, preproinsulin-specific CD8 T-cells primed in anti-B7-H1 antibody-treated B6 mice, or primed in B7-H1(-/-) or PD-1(-/-) mice induced EAD. Immunization of bone marrow chimeric mice showed that deficiency of either B7-H.1 in pancreatic beta-cells or of PD-1 in autoreactive CD8 T-cells induced EAD.

CONCLUSIONS

An imbalance between costimulator (B7.1) and coinhibitor (B7-H1) signals on pancreatic beta-cells can trigger pancreatic beta-cell-destruction by preproinsulin-specific CD8 T-cells. Hence, regulation of the susceptibility of the beta-cells for a preproinsulin-specific CD8 T-cell attack can allow or suppress EAD.

摘要

目的

在表达共刺激分子 B7.1（CD80）的胰岛β细胞上表达 RIP-B7.1 小鼠是一种成熟的模型，可用于鉴定前胰岛素特异性 CD8 T 细胞反应和实验性自身免疫性糖尿病（EAD）。不同的免疫策略可以在野生型 C57BL/6（B6）小鼠中引发前胰岛素特异性 CD8 T 细胞，但不会引起糖尿病。我们测试了改变胰岛β细胞上的 B7-H1（PD-L1）共抑制是否可以揭示前胰岛素特异性 CD8 T 细胞的致糖尿病潜力。

研究设计和方法

使用基于 DNA 的免疫接种和过继性 T 细胞转移来鉴定 RIP-B7.1、B6、B7-H1（-/-）、PD-1（-/-）或骨髓嵌合小鼠中前胰岛素特异性 CD8 T 细胞反应和 EAD 的诱导。

结果

在 B6 小鼠中引发的前胰岛素特异性 CD8 T 细胞在过继转移到同源性 RIP-B7.1 宿主后显示出其致糖尿病潜力。此外，在前胰岛素特异性 CD8 T 细胞用抗 B7-H1 抗体处理的 B6 小鼠中引发或在 B7-H1（-/-）或 PD-1（-/-）小鼠中引发的 EAD。骨髓嵌合小鼠的免疫接种表明，胰岛β细胞中 B7-H.1 或自身反应性 CD8 T 细胞中 PD-1 的缺乏均会引发 EAD。

结论

胰岛β细胞上的共刺激分子（B7.1）和共抑制分子（B7-H1）信号之间的不平衡可能会引发前胰岛素特异性 CD8 T 细胞破坏胰岛β细胞。因此，调节β细胞对前胰岛素特异性 CD8 T 细胞攻击的敏感性可以允许或抑制 EAD。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/641b/2911076/7dbf029ceba1/zdb0081062150004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/641b/2911076/1800f7383e22/zdb0081062150001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/641b/2911076/d4f4052e26c7/zdb0081062150002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/641b/2911076/4e0074906603/zdb0081062150003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/641b/2911076/7dbf029ceba1/zdb0081062150004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/641b/2911076/1800f7383e22/zdb0081062150001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/641b/2911076/d4f4052e26c7/zdb0081062150002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/641b/2911076/4e0074906603/zdb0081062150003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/641b/2911076/7dbf029ceba1/zdb0081062150004.jpg

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