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The role of natural killer cells in autoimmune diabetes

University of British Columbia

Type 1 diabetes (T1D) is caused by the autoimmune destruction of insulin-producing β-cells with consequent hyperglycemia and serious chronic complications. Both innate and adaptive immune responses are involved in the pathogenesis of this disease. Studies in animal models and in patients with T1D have shown that natural killer (NK) cells are involved both in disease progression and in disease protection, thus suggesting that NK cells can represent a potential therapeutic target in this disease, once the contribution of NK cells to islet immunity has been fully elucidated. Using the model of complete Freund’s adjuvant (CFA) injection, which has been reported to efficiently prevent diabetes in non-obese diabetic (NOD) mice, the role of NK cells in diabetes was investigated. Results showed that CFA immunization of NOD mice markedly increased frequency and function of NK cells. Notably, the adoptive transfer of diabetes into NOD/SCID recipients clearly implied that IFNγ secreted from NK cells mediated the protection effect of CFA, suggesting that the NK cell is a critical mediator for diabetes protection. Furthermore, investigation of the mechanism by which CFA activates NK cells found that this activation was through a CD1d-dependent but MyD88-independent pathway. These experiments also showed an up-regulation of NKG2D expression of NK cells and this might possibly be through decreased surface expression of NKG2D ligand. Similar to the NOD mouse, in which NK cells exhibit numeric and functional abnormalities, experiments in peripheral blood mononuclear cells (PBMCs) from patients with T1D also demonstrated that NK cells from T1D patients are present at reduced frequencies and show diminished responsiveness to the cytokines IL-2 and IL-15. Interestingly, cell surface analysis reveals that NKG2D ligands are also expressed on human NK cells and that unlike in non-diabetic controls, T1D NK cells fail to down-regulate NKG2D ligands upon activation by cytokines. Furthermore, NK cells from patients exhibit decreased NKG2D-dependent cytotoxicity and cytokine secretion, as well as reduced NKG2D-mediated signaling pathways. Collectively, these results suggest that NK cell dysfunction and aberrant NKG2D signaling may contribute to the pathogenesis of T1D.

Text

2010-10-14

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/29156

Pathology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/