CRC 4855, Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, 3001 North 12th Avenue, Sherbrooke, Quebec J1H 5N4, Canada.
Diabetologia. 2012 Nov;55(11):3010-20. doi: 10.1007/s00125-012-2675-1. Epub 2012 Aug 14.
AIMS/HYPOTHESIS: IL-15, induced by innate immune stimuli, promotes rheumatoid arthritis and inflammatory bowel disease. However, its role in autoimmune type 1 diabetes is unclear. Our aim is to define the role of IL-15 in the pathogenesis of diabetes in the NOD mouse model.
We generated NOD.Il15(-/-) mice expressing a polyclonal repertoire of T cell antigen receptor (TCR) or a transgenic TCR and monitored diabetes onset and insulitis. NOD Scid.Il15(-/-) (full name NOD.CB17-Prkdc (scid)/NCrCrl) and NOD Scid.gamma (full name NOD.Cg-Prkdc(scid) Il2rg ( tm1Wjl )/SzJ) mice were used to distinguish the requirement for IL-15 signalling in CD8(+) T cells and antigen-presenting cells (APCs) to induce disease. We examined the effect of blocking IL-15 signalling on diabetes onset in NOD mice.
At 7 months of age, more than 75% of the NOD Il15(-/-) female mice remained diabetes free compared with only 30% in the control group. Diabetes incidence was also decreased in 8.3-NOD (full name NOD Cg-Tg[TcraTcrbNY8.3]-1Pesa/DvsJ).Il15(-/-) mice expressing a highly pathogenic transgenic TCR on CD8(+) T cells. Adoptive transfer of splenocytes from diabetic NOD and 8.3-NOD donors induced disease in NOD Scid recipients but not in NOD Scid.Il15(-/-) or NOD Scid.gamma mice. Transient blockade of IL-15 signalling at the onset of insulitis prevented diabetes in NOD mice.
CONCLUSIONS/INTERPRETATION: Our results show that IL-15 is needed for the initial activation of diabetogenic CD8(+) T cells as well as for sustaining the diabetogenic potential of antigen-stimulated cells, acting on both CD8(+) T cells and on APCs. Our findings demonstrate a critical role for IL-15 in the pathogenesis of autoimmune diabetes and suggest that IL-15 is a promising therapeutic target.
目的/假设：IL-15 由先天免疫刺激诱导，促进类风湿关节炎和炎症性肠病。然而，其在自身免疫性 1 型糖尿病中的作用尚不清楚。我们的目的是确定 IL-15 在 NOD 小鼠模型中糖尿病发病机制中的作用。
我们生成了表达多克隆 T 细胞抗原受体（TCR）的 NOD.Il15（-/-）小鼠或转基因 TCR，并监测糖尿病的发病和胰岛炎。使用 NOD Scid.Il15（-/-）（全名 NOD.CB17-Prkdc（scid）/NCrCrl）和 NOD Scid.gamma（全名 NOD.Cg-Prkdc(scid) Il2rg（tm1Wjl）/SzJ）小鼠来区分 IL-15 信号在诱导疾病中对 CD8（+）T 细胞和抗原呈递细胞（APCs）的要求。我们检查了阻断 IL-15 信号对 NOD 小鼠糖尿病发病的影响。
在 7 个月大时，与对照组相比，超过 75%的 NOD Il15（-/-）雌性小鼠仍然没有发生糖尿病，而对照组只有 30%。在表达 CD8（+）T 细胞上高度致病性转基因 TCR 的 8.3-NOD（全名 NOD Cg-Tg[TcraTcrbNY8.3]-1Pesa/DvsJ）。Il15（-/-）小鼠中，糖尿病的发生率也降低了。来自糖尿病 NOD 和 8.3-NOD 供体的脾细胞过继转移可在 NOD Scid 受体中诱导疾病，但不能在 NOD Scid.Il15（-/-）或 NOD Scid.gamma 小鼠中诱导疾病。在胰岛炎发病时短暂阻断 IL-15 信号可预防 NOD 小鼠发生糖尿病。
结论/解释：我们的结果表明，IL-15 既需要初始激活致糖尿病 CD8（+）T 细胞，也需要维持抗原刺激细胞的致糖尿病潜能，作用于 CD8（+）T 细胞和 APC。我们的发现表明 IL-15 在自身免疫性糖尿病的发病机制中起关键作用，并表明 IL-15 是一个有前途的治疗靶点。
