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Yamanouchi, J. et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat. Genet. 39, 329-337

University of Cambridge, Cambridge, England, United Kingdom
Nature Genetics (Impact Factor: 29.65). 04/2007; 39(3):329-37. DOI: 10.1038/ng1958
Source: PubMed

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.

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Available from: Simon G Gregory, Aug 21, 2015
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    • "An example is the IL-2 locus in mouse chromosome 3. Because IL-2 is required to maintain Treg function (Yamanouchi et al., 2007; Wing and Sakaguchi, 2010), T cells from B6 mice produce a higher level of IL-2, and allelic variance of the IL2 locus in chromosome 3 exists between A/J and B6 mice (Del Rio et al., 2008), we hypothesized that resistance to post-vasectomy autoimmunity in B6 mice is due to high IL-2, which strengthens intrinsic Treg function. This hypothesis was supported by the finding that B6 mice developed post-vasectomy autoimmune orchitis after 98% (not 60%) Treg depletion. "
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    ABSTRACT: CD4+ CD25+ regulatory T cells (Tregs) strongly influence the early and late autoimmune responses to meiotic germ cell antigens (MGCA) and the gonadal immunopathology in vasectomized mice. This is supported by the published and recently acquired information presented here. Within 24h of unilateral vasectomy (uni-vx) the ipsilateral epididymis undergoes epithelial cell apoptosis followed by necrosis, severe inflammation, and granuloma formation. Unexpectedly, vasectomy alone induced MGCA-specific tolerance. In contrast, uni-vx plus simultaneous Treg depletion resulted in MGCA-specific autoimmune response and bilateral autoimmune orchitis. Both tolerance and autoimmunity were strictly linked to the early epididymal injury. We now discovered that testicular autoimmunity in uni-vx mice did not occur when Treg depletion was delayed by one week. Remarkably, this delayed Treg depletion also prevented tolerance induction. Therefore, tolerance depends on a rapid de novo Treg response to MGCA exposed after vasectomy. Moreover, tolerance was blunted in mice genetically deficient in PD-1 ligand, suggesting the involvement of induced Treg. We conclude that pre-existing natural Treg prevents post-vasectomy autoimmunity, whereas vasectomy-induced Treg maintains post-vasectomy tolerance. We further discovered that vasectomized mice were still resistant to autoimmune orchitis induction for at least 12-16 months; thus, tolerance is long-lasting. Although significant sperm autoantibodies of low titers became detectable in uni-vx mice at 7 months, the antibody titers fluctuated over time, suggesting a dynamic "balance" between the autoimmune and tolerance states. Finally, we observed severe epididymal fibrosis and hypo-spermatogenesis at 12 months after uni-vx: findings of highly critical clinical significance.
    Journal of Reproductive Immunology 09/2013; 100(1). DOI:10.1016/j.jri.2013.08.004 · 2.37 Impact Factor
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    • "Haplotype mapping analysis has been used to identify a key SNP in the Ctla4 gene, which was then further verified as a causative polymorphism responsible for Idd5.1 (Araki et al. 2009). Similarly, haplotype mapping was of key importance in the verification of the interleukin-2 gene as the basis of Idd3 (Yamanouchi et al. 2007). Therefore, despite the difficulty in resolving the complex Idd9.1/4 and Idd9.2 loci, such genetic mapping studies remain of importance in defining disease susceptibility loci in both mouse and man. "
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    ABSTRACT: Nonobese diabetic (NOD) mice congenic for C57BL/10 (B10)-derived genes in the Idd9 region of chromosome 4 are highly protected from type 1 diabetes (T1D). Idd9 has been divided into three protective subregions (Idd9.1, 9.2, and 9.3), each of which partially prevents disease. In this study we have fine-mapped the Idd9.1 and Idd9.2 regions, revealing further genetic complexity with at least two additional subregions contributing to protection from T1D. Using the NOD sequence from bacterial artificial chromosome clones of the Idd9.1 and Idd9.2 regions as well as whole-genome sequence data recently made available, sequence polymorphisms within the regions highlight a high degree of polymorphism between the NOD and B10 strains in the Idd9 regions. Among numerous candidate genes are several with immunological importance. The Idd9.1 region has been separated into Idd9.1 and Idd9.4, with Lck remaining a candidate gene within Idd9.1. One of the Idd9.2 regions contains the candidate genes Masp2 (encoding mannan-binding lectin serine peptidase 2) and Mtor (encoding mammalian target of rapamycin). From mRNA expression analyses, we have also identified several other differentially expressed candidate genes within the Idd9.1 and Idd9.2 regions. These findings highlight that multiple, relatively small genetic effects combine and interact to produce significant changes in immune tolerance and diabetes onset. Electronic supplementary material The online version of this article (doi:10.1007/s00335-013-9466-y) contains supplementary material, which is available to authorized users.
    Mammalian Genome 08/2013; 24(9-10). DOI:10.1007/s00335-013-9466-y · 2.88 Impact Factor
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    • "Importantly , treatment with low-dose IL-2 preferentially targets regulatory rather than effector T cells, restores Treg expression of CD25 and Foxp3, and can prevent or even reverse diabetes in NOD mice (Tang et al. 2008; Grinberg-Bleyer et al. 2010). In this regard, the IL-2 gene was identified as the likely candidate for susceptibility locus Idd3 in NOD mice, and polymorphisms in the IL-2 gene result in lower levels of IL-2 production (Wicker et al. 1994; Lyons et al. 2000; Yamanouchi et al. 2007). Thus, defective IL-2 production by Teff in pancreatic islets could be responsible for the low CD25 expression and poor survival of Tregs in the tissue. "
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    ABSTRACT: Type 1 Diabetes (T1D), also called juvenile diabetes because of its classically early onset, is considered an autoimmune disease targeting the insulin-producing β cells in the pancreatic islets of Langerhans. T1D reflects a loss of tolerance to tissue self-antigens caused by defects in both central tolerance, which aims at eliminating potentially autoreactive lymphocytes developing in the thymus, and peripheral tolerance, which normally controls autoreactive T cells that escaped the thymus. Like in other autoimmune diseases, the mechanisms leading to T1D are multifactorial and depend on a complex combination of genetic, epigenetic, molecular, and cellular elements that result in the breakdown of peripheral tolerance. In this article, we discuss the contribution of these factors in the development of the autoimmune response targeting pancreatic islets in T1D and the therapeutic strategies currently being explored to correct these defects.
    Cold Spring Harbor Perspectives in Medicine 03/2012; 2(3):a007807. DOI:10.1101/cshperspect.a007807 · 7.56 Impact Factor
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