Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 40, Issue 8, Pages 2267-2276Publisher
WILEY
DOI: 10.1002/eji.201040416
Keywords
Autoimmunity; Costimulation; ICOS; ICOS ligand; Type 1 diabetes
Categories
Funding
- Avenir INSERM
- FRM
- INSERM
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NOD mice spontaneously develop insulin-dependent diabetes around 10-40 wk of age. Numerous immune gene variants contribute to the autoimmune process. However, genes that direct the autoimmune response toward p cells remain ill defined. In this study, we provide evidence that the Icos and Icosl genes contribute to the diabetes process. Protection from diabetes in ICOS-/- and ICOSL-/- NOD mice was unexpectedly associated with the development of an autoimmune disorder of the neuro-muscular system, characterized by myositis, sensory ganglionitis and, to a reduced extent, inflammatory infiltrates in the CNS. This syndrome was reproduced upon adoptive transfer of CD4(+) and CD8(+) T cells from diseased donors to naive NOD.scid recipients. Our data further show that protection from diabetes results from defective activation of autoimmune diabetogenic effector T cells in ICOS-/- NOD mice, whereas acceleration of diabetes in BDC2.5 ICOS-/- NOD mice is induced by a dominant defect in Treg. Taken together, our findings indicate that costimulation signals play a key role in regulating immune tolerance in peripheral tissues and that the ICOS/ICOSL costimulatory pathway influences the balance between Treg and diabetogenic effector T cells.
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