Article abstract
Nature Genetics 39, 329 - 337 (2007)
Published online: 4 February 2007 | doi:10.1038/ng1958
Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity
Jun Yamanouchi1, Dan Rainbow2, Pau Serra1, Sarah Howlett2, Kara Hunter2, Valerie E S Garner2, Andrea Gonzalez-Munoz2, Jan Clark2, Riitta Veijola2, Rose Cubbon3, Show-Ling Chen3, Raymond Rosa3, Anne Marie Cumiskey3, David V Serreze4, Simon Gregory5, Jane Rogers5, Paul A Lyons2, Barry Healy2, Luc J Smink2, John A Todd2, Laurence B Peterson3, Linda S Wicker2,6 & Pere Santamaria1,6
Abstract
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.
- Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology and Infectious Diseases, Institute of Inflammation, Infection and Immunity, Faculty of Medicine, The University of Calgary, Calgary, Alberta T2N 4N1, Canada.
- Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, UK.
- Merck Research Laboratories, Rahway, New Jersey 07065, USA.
- The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
- Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.
- These authors contributed equally to this work.
Correspondence to: Pere Santamaria1,6 e-mail: psantama@ucalgary.ca
Correspondence to: Linda S Wicker2,6 e-mail: linda.wicker@cimr.cam.ac.uk
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