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Interleukin-15 plays an essential role in the pathogenesis of autoimmune diabetes in the NOD mouse. Diabetologia 2012 Nov;55(11):3010-20

Date

08/15/2012

Pubmed ID

22890824

DOI

10.1007/s00125-012-2675-1

Scopus ID

2-s2.0-84867571600   30 Citations

Abstract

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.

METHODS: 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.

RESULTS: 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.

Author List

Bobbala D, Chen XL, Leblanc C, Mayhue M, Stankova J, Tanaka T, Chen YG, Ilangumaran S, Ramanathan S

Author

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adoptive Transfer
Animals
Autoimmunity
CD8-Positive T-Lymphocytes
Cell Communication
Cell Survival
Diabetes Mellitus, Type 1
Disease Models, Animal
Female
Interleukin-15
Male
Mice
Mice, Inbred NOD
Mice, SCID
Mice, Transgenic
Prediabetic State
Signal Transduction
T-Lymphocytes, Cytotoxic