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J Autoimmun. 2013 Feb;40:66-73. doi: 10.1016/j.jaut.2012.08.001. Epub 2012 Sep 1.

NKG2D blockade facilitates diabetes prevention by antigen-specific Tregs in a virus-induced model of diabetes.

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Type 1 Diabetes Center of San Diego, La Jolla Institute for Allergy and Immunology, La Jolla, 9420 Athena Circle, San Diego, CA 92037, USA.


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.

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