Natural Killer Cells From Children With Type 1 Diabetes Have Defects in NKG2D-Dependent Function and Signaling

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 3; pp. 857 - 866
• Main Authors: Qin, Huilian, Lee, I-Fang, Panagiotopoulos, Constadina, Wang, Xiaoxia, Chu, Alvina D., Utz, Paul J., Priatel, John J., Tan, Rusung
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2011
• Subjects: Adolescent; Analysis; Analysis of Variance; Biological and medical sciences; Care and treatment; Cells; Cells, Cultured; Cellular signal transduction; Child; Cloning; Cytokines; Cytotoxicity; Diabetes; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Diabetes. Impaired glucose tolerance; Disease; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Flow Cytometry; Genetic aspects; Health aspects; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; Humans; Immunology and Transplantation; Interleukin-15 - immunology; Interleukin-15 - metabolism; Interleukin-15 - pharmacology; Interleukin-2 - immunology; Interleukin-2 - metabolism; Interleukin-2 - pharmacology; Killer cells; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Kinases; Ligands; Lymphocyte Count; Medical sciences; NK Cell Lectin-Like Receptor Subfamily K - immunology; NK Cell Lectin-Like Receptor Subfamily K - metabolism; Pathogenesis; R&D; Research & development; Research design; Risk factors; Signal Transduction - physiology; Type 1 diabetes; Womens health; Canada; United States; Endocrinopathy; Human; Natural killer cell; Immunopathology; Signal transduction; Type 1 diabetes; Autoimmune disease; Child
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db09-1706

Natural killer (NK) cells from NOD mice have numeric and functional abnormalities, and restoration of NK cell function prevents autoimmune diabetes in NOD mice. However, little is known about the number and function of NK cells in humans affected by type 1 diabetes. Therefore, we evaluated the phenotype and function of NK cells in a large cohort of type 1 diabetic children. Peripheral blood mononuclear blood cells were obtained from subjects whose duration of disease was between 6 months and 2 years. NK cells were characterized by flow cytometry, enzyme-linked immunosorbent spot assays, and cytotoxicity assays. Signaling through the activating NK cell receptor, NKG2D, was assessed by immunoblotting and reverse-phase phosphoprotein lysate microarray. NK cells from type 1 diabetic subjects were present at reduced cell numbers compared with age-matched, nondiabetic control subjects and had diminished responses to the cytokines interleukin (IL)-2 and IL-15. Analysis before and after IL-2 stimulation revealed that unlike NK cells from nondiabetic control subjects, NK cells from type 1 diabetic subjects failed to downregulate the NKG2D ligands, major histocompatibility complex class I-related chains A and B, upon activation. Moreover, type 1 diabetic NK cells also exhibited decreased NKG2D-dependent cytotoxicity and interferon-γ secretion. Finally, type 1 diabetic NK cells showed clear defects in NKG2D-mediated activation of the phosphoinositide 3-kinase-AKT pathway. These results are the first to demonstrate that type 1 diabetic subjects have aberrant signaling through the NKG2D receptor and suggest that NK cell dysfunction contributes to the autoimmune pathogenesis of type 1 diabetes.