title: NKG2D blockade facilitates diabetes prevention by antigen-specific Tregs in a virus-induced model of diabetes.
abstract: 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.
authors.affiliation: Type 1 Diabetes Center of San Diego, La Jolla Institute for Allergy and Immunology, La Jolla, 9420 Athena Circle, San Diego, CA 92037, USA.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Van Belle
authors.forename: Ellie
authors.initials: E
authors.lastname: Ling
authors.forename: Claus
authors.initials: C
authors.lastname: Haase
authors.forename: Damien
authors.initials: D
authors.lastname: Bresson
authors.forename: Birgitte
authors.initials: B
authors.lastname: Ursø
authors.forename: Matthias G
authors.initials: MG
authors.lastname: von Herrath
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D007694:Killer Cells, Natural / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology / Q000378:metabolism*; D034521:Nuclear Matrix-Associated Proteins / Q000096:biosynthesis; D029543:Nucleocytoplasmic Transport Proteins / Q000096:biosynthesis; D010179:Pancreas / Q000276:immunology / Q000821:virology; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000906:Antibodies; C527086:Klrk1 protein, mouse; D055655:NK Cell Lectin-Like Receptor Subfamily K; D034521:Nuclear Matrix-Associated Proteins; D029543:Nucleocytoplasmic Transport Proteins; C490521:Rae1 protein, mouse