Journal
DIABETOLOGIA
Volume 55, Issue 11, Pages 3010-3020Publisher
SPRINGER
DOI: 10.1007/s00125-012-2675-1
Keywords
IL-15; Insulitis; NOD mice; Type 1 diabetes
Categories
Funding
- JDRF Innovative award [5-2010-608]
- Canadian Institutes of Health Research [MOP-86530]
- Fonds de la Recherche en Sante du Quebec
- Grants-in-Aid for Scientific Research [22590440] Funding Source: KAKEN
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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. 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.
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