Semeraro Michele L, Glenn Lindsey M, Morris Margaret A
Department of Internal Medicine, Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, VA, United States.
Front Endocrinol (Lausanne). 2017 Sep 25;8:246. doi: 10.3389/fendo.2017.00246. eCollection 2017.
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] 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.
自然杀伤（NK）细胞是对抗病毒感染的重要效应细胞群，越来越多的证据表明，病毒感染在至少一部分1型糖尿病（T1D）患者的发病过程中起作用。NK细胞通过其表面抑制性和刺激性受体之间的微妙平衡来识别靶细胞。如果这种平衡失调，由于大多数NK细胞表面存在的活化NKp46受体与尚未明确的NKp46配体在β细胞上的表达相互作用，NK细胞极有可能在胰腺中造成严重破坏。阻断NKp46与其配体之间的相互作用可保护小鼠免受链脲佐菌素诱导的糖尿病影响，但尚未对非糖尿病和糖尿病供体样本中的差异表达进行检测。其他研究表明，人类T1D患者外周血NK细胞的表型发生了改变，降低了NK细胞的裂解和功能能力。对人类T1D胰腺组织的研究表明，尽管NK细胞很少被检测到，但它们的存在可能是有益的。在非肥胖糖尿病（NOD）小鼠中，我们注意到NK细胞表达高水平的促炎介质12/15-脂氧合酶（12/15-LO），而刺激性受体水平降低。相反，免受糖尿病发展影响的12/15-LO缺陷型NOD小鼠的NK细胞表达的刺激性受体水平显著更高。此外，人类NK92细胞系通过蛋白质印迹法表达ALOX12蛋白[人类12-脂氧合酶（12-LO），与小鼠12/15-LO相关]。在含有胰岛素的胰岛存在的情况下，人类12-LO在T1D和T2D人类供体的胰腺中均上调，表明12-LO表达与糖尿病进展之间存在联系。因此，我们的假设是，由于12-LO表达和活化增加，易患T1D的个体中的NK细胞在胰腺β细胞病毒感染期间无法正常发挥功能，这导致干扰素-γ产生增加以及NK细胞活化和抑制受体失衡，并可能导致下游自身免疫性T细胞反应。本文介绍的工作概述了来自我们实验室以及已发表文献的证据，包括新数据，以支持我们的假设。
