Type 1 Diabetes Center of San Diego, La Jolla Institute for Allergy and Immunology, La Jolla, 9420 Athena Circle, San Diego, CA 92037, USA.
J Autoimmun. 2013 Feb;40:66-73. doi: 10.1016/j.jaut.2012.08.001. Epub 2012 Sep 1.
It is thought that viral infections might jeopardize regulatory T cell therapy in type 1 diabetes. Viral infections can lead to surface expression of ligands for the activating NKG2D receptor, such as retinoic acid early transcript 1 (Rae-1), whose expression on beta-cells recruits NKG2D(+) autoreactive CD8(+) T cells. Both in men and mice, autoreactive cytotoxic T cells express NKG2D. We showed that NKG2D expression increased on CD4(+) and CD8(+) T cells during virus-induced diabetes development in the rat insulin promotor (RIP) Lymphocytic Choriomeningitis Virus (LCMV) model. Combination treatment with anti-NKG2D and antigen-specific regulatory T cells (Treg), at doses inefficacious in mono-treatment, synergized to prevent diabetes in 75% of the virus-infected RIP-LCMV mice. Nevertheless, NKG2D blockade alone failed to reverse recent-onset diabetes in non-obese diabetic (NOD) mice, despite downregulation of NKG2D on NK cells in the blood and CD8(+) T cells in the spleen and pancreatic lymph nodes. Our data suggest that blocking the interaction of NKG2D with it ligands is insufficient to protect against diabetes when a strong inflammatory process actively drives NKG2D upregulation, but should be considered to help maintaining Treg functionality during ongoing pancreatic inflammation.
据认为，病毒感染可能危及 1 型糖尿病的调节性 T 细胞治疗。病毒感染可导致激活的 NKG2D 受体配体的表面表达，如维甲酸早期转录物 1（Rae-1），其在β细胞上的表达募集 NKG2D(+)自身反应性 CD8(+)T 细胞。在男性和小鼠中，自身反应性细胞毒性 T 细胞表达 NKG2D。我们表明，在大鼠胰岛素启动子（RIP）淋巴细胞性脉络丛脑膜炎病毒（LCMV）模型中，病毒诱导的糖尿病发展过程中，CD4(+)和 CD8(+)T 细胞上的 NKG2D 表达增加。在与抗原特异性调节性 T 细胞（Treg）联合治疗时，NKG2D 表达增加，在单药治疗无效的剂量下，协同作用可预防 75%感染病毒的 RIP-LCMV 小鼠发生糖尿病。然而，尽管在血液中的 NK 细胞和脾脏和胰腺淋巴结中的 CD8(+)T 细胞中 NKG2D 的下调，NKG2D 阻断单独治疗也未能逆转非肥胖型糖尿病（NOD）小鼠的新发糖尿病。我们的数据表明，当强烈的炎症过程积极上调 NKG2D 时，阻断 NKG2D 与其配体的相互作用不足以预防糖尿病，但应考虑在持续的胰腺炎症期间帮助维持 Treg 功能。
