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Autoimmune diseases are thought to result from imbalances in normal immune physiology and regulation. Here, we show that autoimmune disease susceptibility and resistance alleles on mouse chromosome 3 (Idd3) correlate with differential expression of the key immunoregulatory cytokine interleukin-2 (IL-2). In order to test directly that an approximately twofold reduction in IL-2 underpins the Idd3-linked destabilization of immune homeostasis, we show that engineered haplodeficiency of Il2 gene expression not only reduces T cell IL-2 production by twofold but also mimics the autoimmune dysregulatory effects of the naturally occurring susceptibility alleles of Il2. Reduced IL-2 production achieved by either genetic mechanism correlates with reduced function of CD4(+) CD25(+) regulatory T cells, which are critical for maintaining immune homeostasis.

Original publication

DOI

10.1038/ng1958

Type

Journal article

Journal

Nat Genet

Publication Date

03/2007

Volume

39

Pages

329 - 337

Keywords

Alleles, Animals, Autoimmunity, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Diabetes Mellitus, Type 1, Homeostasis, Interleukin-2, Mice, Mice, Congenic, Mice, Inbred NOD, T-Lymphocytes, Regulatory, Transcription, Genetic