Abstract
Natural killer (NK) cells represent an important effector arm against viral infection, and mounting evidence suggests that viral infection plays a role in the development of type 1 diabetes (T1D) in at least a portion of patients. NK cells recognize their target cells through a delicate balance of inhibitory and stimulatory receptors on their surface. If unbalanced, NK cells have great potential to wreak havoc in the pancreas due to the beta cell expression of the as-yet-defined NKp46 ligand through interactions with the activating NKp46 receptor found on the surface of most NK cells. Blocking interactions between NKp46 and its ligand protects mice from STZ-induced diabetes, but differential expression non-diabetic and diabetic donor samples have not been tested. Additional studies have shown that peripheral blood NK cells from human T1D patients have altered phenotypes that reduce the lytic and functional ability of the NK cells. Investigations of humanT1D pancreas tissues have indicated that the presence of NK cells may be beneficial despite their infrequent detection. In non-obese diabetic (NOD) mice, we have noted that NK cells express high levels of the proinflammatory mediator 12/15-lipoxygenase (12/15-LO), and decreased levels of stimulatory receptors. Conversely, NK cells of 12/15-LO deficient NOD mice, which are protected from diabetes development, express significantly higher levels of stimulatory receptors. Furthermore, the human NK92 cell line expresses the ALOX12 protein [human 12-lipoxygenase (12-LO), related to mouse 12/15-LO] via Western blotting. Human 12-LO is upregulated in the pancreas of both T1D and T2D human donors with insulin-containing islets, showing a link between 12-LO expression and diabetes progression. Therefore, our hypothesis is that NK cells in those susceptible to developing T1D are unable to function properly during viral infections of pancreatic beta cells due to increased 12-LO expression and activation, which contributes to increased interferon-gamma production and an imbalance in activating and inhibitory NK cell receptors, and may contribute to downstream autoimmune T cell responses. The work presented here outlines evidence from our lab, as well as published literature, supporting our hypothesis, including novel data.
Highlights
Autoimmune destruction of the pancreatic beta cells leads to the development of Type 1 diabetes (T1D)
We hypothesize that the activation of Natural killer (NK) cell 12/15-LO (Alox15, in mice) or 12-LO (ALOX12, in humans) through environmental triggers, such as Coxsackievirus infection, contributes to type 1 diabetes (T1D) initiation by affecting the normal innate immune interplay between NK cells and islets, which primes downstream autoimmune responses leading to islet destruction
We have hypothesized that activation of NK cell 12/15-LO contributes to T1D initiation by affecting the normal innate immune interplay between NK cells and islets, which primes downstream autoimmune responses leading to islet destruction
Summary
Autoimmune destruction of the pancreatic beta cells leads to the development of Type 1 diabetes (T1D). Class II HLA genes, especially DR3, DR4, and DQ8, are the strongest links; HLA Class I molecules play a role in diabetes development [2, 3] Expression of both Class I and Class II molecules is the largest contributing factor in determining the immune response to a given pathogen, as peptides are processed and presented to T and natural killer (NK) cells via the proteins of the major histocompatibility complex (MHC) locus [4]. Debates persist as to whether islets are independently inflamed prior to the autoimmune response or the autoimmune response brings about the islet inflammation One of these recent studies described the incorrect processing of the insulin protein that led to the generation of abnormal peptides recognized by circulating CD8+ T cells in T1D patients [8]. Are either islets or immune cells in susceptible individuals causing the initial insults that spark diabetes development, or does an environmental factor trigger the disease? Do we see signs of virus infections in patients with T1D because the infection is what precipitates diabetes development, or are patients with diabetes more susceptible to developing virus infections because of defects in their bodies’ defense systems? With the data that are currently available, the order of events in the precipitation of T1D is unclear
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