title: Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity.
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.
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Yamanouchi
authors.forename: Dan
authors.initials: D
authors.lastname: Rainbow
authors.forename: Pau
authors.initials: P
authors.lastname: Serra
authors.forename: Sarah
authors.initials: S
authors.lastname: Howlett
authors.forename: Kara
authors.initials: K
authors.lastname: Hunter
authors.forename: Valerie E S
authors.initials: VE
authors.lastname: Garner
authors.forename: Andrea
authors.initials: A
authors.lastname: Gonzalez-Munoz
authors.forename: Jan
authors.initials: J
authors.lastname: Clark
authors.forename: Riitta
authors.initials: R
authors.lastname: Veijola
authors.forename: Rose
authors.initials: R
authors.lastname: Cubbon
authors.forename: Show-Ling
authors.initials: SL
authors.lastname: Chen
authors.forename: Raymond
authors.initials: R
authors.lastname: Rosa
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Cumiskey
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze
authors.forename: Simon
authors.initials: S
authors.lastname: Gregory
authors.forename: Jane
authors.initials: J
authors.lastname: Rogers
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lyons
authors.forename: Barry
authors.initials: B
authors.lastname: Healy
authors.forename: Luc J
authors.initials: LJ
authors.lastname: Smink
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Peterson
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
mesh_terms: D000483:Alleles; D000818:Animals; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006706:Homeostasis / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D051379:Mice; D020297:Mice, Congenic; D016688:Mice, Inbred NOD; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D007376:Interleukin-2