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: 29.35). 04/2007; 39(3):329-37. DOI: 10.1038/ng1958
Source: PubMed


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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    • "Protective alleles in Idd3 reduce type 1 diabetes frequency and Il2 and Il21 are the prime candidate genes. The protective effects of Idd3 are evident in multiple cell types including antigen-presenting cells, effector T cells and regulatory (FoxP3+) T cells which are critical for maintaining immune cell homeostasis [12], [13]. "
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    ABSTRACT: Inhibition of PD1-PDL1 signaling in NOD mice accelerates onset of type 1 diabetes implicating this pathway in suppressing the emergence of pancreatic beta cell reactive T-cells. However, the molecular mechanism by which PD1 signaling protects from type 1 diabetes is not clear. We hypothesized that differential susceptibility of Idd mouse strains to type 1 diabetes when challenged with anti PDL1 will identify genomic loci that collaborate with PD1 signaling in suppressing type 1 diabetes. Anti PDL1 was administered to NOD and various Idd mouse strains at 10 weeks of age and onset of disease was monitored by measuring blood glucose levels. Additionally, histological evaluation of the pancreas was performed to determine degree of insulitis. Statistical analysis of the data was performed using Log-Rank and Student's t-test. Blockade of PDL1 rapidly precipitated type 1 diabetes in nearly all NOD Idd congenic strains tested, despite the fact that all are moderately (Idd5, Idd3 and Idd10/18) or highly (Idd3/10/18 and Idd9) protected from spontaneous type 1 diabetes by virtue of their protective Idd genes. Only the Idd3/5 strain, which is nearly 100% protected from spontaneous disease, remained normoglycemic following PDL1 blockade. These results indicate that multiple Idd loci collaborate with PD1 signaling. Anti PDL1 treatment undermines a large portion of the genetic protection mediated by Idd genes in the NOD model of type 1 diabetes. Basal insulitis correlated with higher susceptibility to type 1 diabetes. These findings have important implications since the PD1 pathway is a target for immunotherapy.
    PLoS ONE 02/2014; 9(2):e89561. DOI:10.1371/journal.pone.0089561 · 3.23 Impact Factor
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    • "One such example is the human T1D patient and the non-obese diabetic (NOD) mouse. Both NOD mice and human T1D patients have polymorphisms in the il2, il2ra and il2rb genes which have been correlated with lower production of IL-2 and lower levels of IL-2 signaling [47]–[49]. For the most part, loss of IL-2 signaling in these hosts has been attributed to loss of Treg cell development, maintenance and suppressive function leading to lethal autoimmunity [28], [50]. "
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    ABSTRACT: Optimal T cell activation and expansion require binding of the common gamma-chain (γc) cytokine Interleukin-2 (IL-2) to its cognate receptor that in turn engages a γc/Janus tyrosine kinase (Jak)3 signaling pathway. Because of its restricted expression by antigen-activated T cells and its obligatory role in promoting their survival and proliferation, IL-2 has been considered as a selective therapeutic target for preventing T cell mediated diseases. However, in order to further explore IL-2 targeted therapy, it is critical to precisely understand its role during early events of T cell activation. In this study, we delineate the role of IL-2 and other γc cytokines in promoting the survival of CD4 and CD8 T cells during early phases of priming. Under IL-2 inhibitory conditions (by neutralizing anti-IL-2 mAbs), the survival of activated CD8(+) T cells was reduced, whereas CD4(+) T cells remained much more resistant. These results correlated with reduced Bcl-2 expression, and mitochondrial membrane potential in CD8(+) T cells in comparison to CD4(+) T cells. However, using transwell co-culture assays we have found that CD4(+) T cells could rescue the survival of CD8(+) T cells even under IL-2 deprived conditions via secretion of soluble factors. A cytokine screen performed on CD8(+) T cells cultured alone revealed that IL-21, another γc cytokine, was capable of rescuing their survival under IL-2 deprivation. Indeed, blocking the IL-21 signaling pathway along with IL-2 neutralization resulted in significantly reduced survival of both CD4(+) and CD8(+) T cells. Taken together, we have shown that under IL-2 deprivation conditions, IL-21 may act as the major survival factor promoting T cell immune responses. Thus, investigation of IL-2 targeted therapies may need to be revisited to consider blockade of the IL-21 signaling pathways as an adjunct to provide more effective control of T cell immune responses.
    PLoS ONE 01/2014; 9(1):e85882. DOI:10.1371/journal.pone.0085882 · 3.23 Impact Factor
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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 · 2.82 Impact Factor
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