Interleukin-15 plays an essential role in the pathogenesis of autoimmune diabetes in the NOD mouse.
OBJECTIVE
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
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.
CRC 4855, Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, 3001 North 12th Avenue, Sherbrooke, Quebec J1H 5N4, Canada.
D
D
Bobbala
X-L
XL
Chen
C
C
Leblanc
M
M
Mayhue
J
J
Stankova
T
T
Tanaka
Y-G
YG
Chen
S
S
Ilangumaran
S
S
Ramanathan
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D019409:Interleukin-15 / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D011236:Prediabetic State / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*
D019409:Interleukin-15