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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    • "Idd3 on mouse chromosome 3 has a major effect on diabetes in NOD mice and mouse models of MS, disrupting the balance between the pathogenic autoreactive lymphocyte activation and T reg suppression[131]. The Idd3 region encodes 5 known candidates (Tenr, Il2, Il21, Cetn4, and Fgf2), but studies that recapitulate the reduced amount of IL-2 observed in NOD mice suggest reduced IL-2 impairs the maintenance of T reg cells, particularly in the inflamed pancreas[132]. Because IL-2 is required for the stability of Foxp3 expression, the neutralization of IL-2 exacerbates diabetes development in NOD mice because of fewer CD25 + T regs[133]. "
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    ABSTRACT: Type 1 diabetes is an autoimmune disease that results from the defective induction or maintenance of T cell tolerance against islet b cell self-antigens. Under steady-state conditions, dendritic cells with tolerogenic properties are critical for peripheral immune tolerance. Tolerogenic dendritic cells can induce T cell anergy and deletion and, in some contexts, induce or expand regulatory T cells. Dendritic cells contribute to both immunomodulatory effects and triggering of pathogenesis in type 1 diabetes. This immune equilibrium is affected by both genetic and environmental factors that contribute to the development of type 1 diabetes. Genome-wide association studies and disease association studies have identified .50 polymorphic loci that lend susceptibility or resistance to insulin-dependent diabetes mellitus. In parallel, diabetes susceptibility regions known as insulin-dependent diabetes loci have been identified in the nonobese diabetic mouse, a model for human type 1 diabetes, providing a better understanding of potential immunomodulatory factors in type 1 diabetes risk. Most genetic candidates have annotated immune cell functions, but the focus has been on changes to T and B cells. However, it is likely that some of the genomic susceptibility in type 1 diabetes directly interrupts the tolerogenic potential of dendritic cells in the pathogenic context of ongoing autoimmunity. Here, we will review how gene polymorphisms associated with autoimmune diabetes may influence dendritic cell development and maturation processes that could lead to alterations in the tolerogenic function of dendritic cells. These insights into potential tolerogenic and pathogenic roles for dendritic cells have practical implications for the clinical manipulation of dendritic cells toward tolerance to prevent and treat type 1 diabetes.
    Full-text · Article · Jan 2016 · Journal of Leukocyte Biology
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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.
    Full-text · Article · Feb 2014 · PLoS ONE
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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.
    Full-text · Article · Jan 2014 · PLoS ONE
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