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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.

SUBMITTER: Yamanouchi J

PROVIDER: S-EPMC2886969 | biostudies-literature | 2007 Mar

REPOSITORIES: biostudies-literature

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

Yamanouchi Jun J Rainbow Dan D Serra Pau P Howlett Sarah S Hunter Kara K Garner Valerie E S VE Gonzalez-Munoz Andrea A Clark Jan J Veijola Riitta R Cubbon Rose R Chen Show-Ling SL Rosa Raymond R Cumiskey Anne Marie AM Serreze David V DV Gregory Simon S Rogers Jane J Lyons Paul A PA Healy Barry B Smink Luc J LJ Todd John A JA Peterson Laurence B LB Wicker Linda S LS Santamaria Pere P

Nature genetics 20070204 3

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 expr ...[more]

PMID: 17277778

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Project description:BACKGROUND:Recent studies have shown a crucial role of G?q in immune regulation, but how G?q modulates regulatory B-cell (Breg) function is still unclear. We address this here. METHODS:CD19+IL-10+ Bregs of wild-type (WT) and Gnaq-/- mice were analyzed by flow cytometry after stimulation by lipopolysaccharide. The WT and Gnaq-/- Bregs were isolated and cocultured with WT CD4+CD25- T cells in the presence of T-activator, and the proliferation of T cells and differentiation of regulatory T cells (Tregs) were analyzed by flow cytometry. We used inhibitors of PI3 kinase (PI3K), extracellular regulated protein kinases 1/2 (Erk1/2), and p38 mitogen-activated protein kinase (p38 MAPK) to detect the pathways involved in the regulation of G?q on Breg differentiation, which were confirmed by western blot analysis. Furthermore, the expression level of G?q was assessed by quantitative real-time PCR in peripheral blood mononuclear cells (PBMCs) from healthy controls and rheumatoid arthritis patients. The frequency of CD19+CD24hiCD38hi B cells in PBMCs was detected by flow cytometry, and the association of the G?q mRNA expression level and the frequency of CD19+CD24hiCD38hi B cells was analyzed by Spearman test. RESULTS:The differentiation of CD19+IL-10+ Bregs was inhibited in the Gnaq-/- mice. In addition, G?q depletion showed an impaired suppressive function of Bregs on T-cell proliferation, which might be due to the decreased Treg expansion. Mechanically, our data demonstrated that the PI3K, Erk1/2, and p38 MAPK signaling pathways were required for regulation of G?q on Bregs, and blockage of these signaling pathways impaired Breg differentiation. Consistent with our previous studies, we also found a decreased frequency of CD19+CD24hiCD38hi Bregs in rheumatoid arthritis patients. As expected, a significantly positive correlation was investigated between CD19+CD24hiCD38hi Bregs with G?q mRNA expression. CONCLUSIONS:Our results indicate that G?q plays a critical role in the differentiation and immunosuppression of Bregs, and it may provide a new therapeutic target for autoimmune diseases.

Dataset Information

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

Publications

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

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