Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity.

Publisher: Nature Pub. Co Country of Publication: United States NLM ID: 9216904 Publication Model: Print-Electronic Cited Medium: Print ISSN: 1061-4036 (Print) Linking ISSN: 10614036 NLM ISO Abbreviation: Nat Genet Subsets: MEDLINE

Original Publication: New York, NY : Nature Pub. Co., c1992-

Autoimmunity/*genetics ; Diabetes Mellitus, Type 1/*immunology ; Interleukin-2/*genetics ; T-Lymphocytes, Regulatory/*immunology; Alleles ; Animals ; Autoimmunity/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Diabetes Mellitus, Type 1/genetics ; Diabetes Mellitus, Type 1/metabolism ; Homeostasis/immunology ; Interleukin-2/biosynthesis ; Interleukin-2/immunology ; Mice ; Mice, Congenic ; Mice, Inbred NOD ; T-Lymphocytes, Regulatory/metabolism ; Transcription, Genetic

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.

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United Kingdom WT_ Wellcome Trust; 061859 United Kingdom WT_ Wellcome Trust

Indexing Agency: NLM Local ID #: UKMS31085.

0 (Interleukin-2)

Date Created: 20070206 Date Completed: 20070620 Latest Revision: 20240608

20240608

PMC2886969

10.1038/ng1958

17277778