Generalized autoimmune disease in interleukin‐2‐deficient mice is triggered by an uncontrolled activation and proliferation of CD4<sup>+</sup> T cells

Sadlack, Benjamin; Löhler, Jürgen; Schorle, Hubert; Klebb, Gabriele; Haber, Hildegard; Sickel, E.; Noelle, Randolph J.; Horak, Ivan D.

doi:10.1002/eji.1830251111

Cited by 398 publications

(293 citation statements)

References 21 publications

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“…IL-2 was originally identified as an important T cell growth factor in vitro [19]. Paradoxically, strong T cell hyperproliferation and autoimmune diseases are observed in mice deficient for IL-2 or components of its receptor [20][21][22][23]. This unexpected pathology can be explained by a reduced number of Treg or their functional impairment [24][25][26][27][28][29], since transfer of wildtype Treg into neonatal IL-2R-deficient mice prevents disease development [24,26,28,30].…”

Section: Il-2 Is Essential For Treg Homeostasismentioning

confidence: 99%

Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango

2005

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Although CD4 + CD25 + regulatory T cells (Treg) represent a well-characterized population of T cells with in vitro and in vivo suppressive capacity, the basic mechanisms of suppression are still not understood. The constitutive expression of the high-affinity receptor for IL-2 has raised the question about the role of IL-2 in Treg function. Here, we review recent data indicating that IL-2 is not only necessary for the homeostasis of Treg but is also critical for the activation of Treg function. Since Treg do not produce IL-2 by themselves, their capacity to utilize IL-2 secreted by other T cells appears to be an essential component of Treg biology. This indicates that Treg suppressive activity is controlled by interaction with activated target cells via the soluble mediator IL-2. In Treg, IL-2 has been identified as a potent inducer of the immunosuppressive cytokine IL-10, an important mediator of Treg suppression in vivo. The efficient capture of IL-2 by Treg may, under conditions of limited IL-2 supply, cause IL-2 deprivation of responder T cells. This competition can explain some of the currently discussed discrepancies between in vivo and in vitro activity of Treg.

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Section: Il-2 Is Essential For Treg Homeostasismentioning

confidence: 99%

Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango

2005

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“…Furthermore, the generation of mice deficient in IL-2 or its receptor has highlighted the importance of IL-2 in regulatory T cell (Treg) development. Both IL-2-and IL-2R-deficient mice are prone to develop autoimmunity and may develop lymphoproliferative diseases [12][13][14][15][16][17]. Thus, IL-2 is implicated in promoting as well as inhibiting T cell responses [18].…”

Section: Introductionmentioning

confidence: 99%

Differential role of IL‐2R signaling for CD8⁺ T cell responses in acute and chronic viral infections

Bachmann¹,

et al. 2007

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IL‐2 is a cytokine with multiple and even divergent functions; it has been described as a key cytokine for in vitro T cell proliferation but is also essential for down‐regulating T cell responses by inducing activation‐induced cell death as well as regulatory T cells. The in vivo analysis of IL‐2 function in regulating specific T cell responses has been hampered by the fact that mice deficient in IL‐2 or its receptors develop lymphoproliferative diseases and/or autoimmunity. Here we generated chimeric mice harboring both IL‐2R‐competent and IL‐2R‐deficient T cells and assessed CD8+ T cell induction, function and maintenance after acute or persistent viral infections. Induction and maintenance of CD8+ T cells were relatively independent of IL‐2R signaling during acute/resolved viral infection. In marked contrast, IL‐2 was crucial for secondary expansion of memory CD8+ T cells and for the maintenance of virus‐specific CD8+ T cells during persistent viral infections. Thus, depending on the chronicity of antigen exposure, IL‐2R signaling is either essential or largely dispensable for induction and maintenance of virus‐specific CD8+ T cell responses.

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“…Genetic lesions in the Foxp3 gene (the scurfy mutant mouse or human patients with immune dysfunction/polyendocrinopathy/enteropathy/X-linked syndrome) lack Treg and develop a fatal autoimmune lymphoproliferative disease [1][2][3][4][5][6][7]. A similar, but less severe, phenotype is observed in mice deficient in IL-2 and components of its receptor complex, CD25 and CD122 [8][9][10][11][12]. Thus, disrupting the IL-2R signaling pathway results in severe T cell-mediated autoimmunity rather than immune deficiency, indicating a significant role for IL-2R signaling in Treg development and function.…”

Section: Introductionmentioning

confidence: 99%

IL‐2Rβ links IL‐2R signaling with Foxp3 expression

2007

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Immunological tolerance to self antigens is a tightly regulated process. Recent work has demonstrated that the forkhead family member Foxp3 is a critical element in the differentiation and function of mouse CD4 + CD25 + regulatory T cells (Treg). Recent work has suggested an important role for IL-2 in the development and maintenance of Treg. To directly assess the effect of IL-2 signaling on Treg development and function, we analyzed mice that were genetically deficient in components of the IL-2 receptor (IL-2R). Mice lacking CD25 (IL-2Ra) displayed a slight decrease in Treg within the thymus, while peripheral numbers are unchanged. In contrast, we found that mice deficient in CD122 (IL-2Rb) had a profound reduction in both thymic and peripheral Treg, coinciding with more rapid development of a fatal lymphoproliferative disease. Expression of a Foxp3 transgene restored Treg and protected against the onset of autoimmunity. Thus, a signal mediated by IL-2Rb is essential for the development and homeostasis of Foxp3 + Treg in vivo.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2007/37101_s.pdf IntroductionPeripheral tolerance to self antigens is regulated, in part, by a population of CD4 + CD25 + Foxp3 + regulatory T cells (Treg). Genetic lesions in the Foxp3 gene (the scurfy mutant mouse or human patients with immune dysfunction/polyendocrinopathy/enteropathy/X-linked syndrome) lack Treg and develop a fatal autoimmune lymphoproliferative disease [1][2][3][4][5][6][7]. A similar, but less severe, phenotype is observed in mice deficient in IL-2 and components of its receptor complex, . Thus, disrupting the IL-2R signaling pathway results in severe T cell-mediated autoimmunity rather than immune deficiency, indicating a significant role for IL-2R signaling in Treg development and function.Signaling through the IL-2R complex is initiated by ligand-induced heterodimerization of CD122 and CD132, which activates the associated tyrosine kinases JAK1 and JAK3. Since it has previously been shown that a covalently linked JAK3 molecule can functionally replace the cytoplasmic domain of CD132, the role of CD132 in IL-2R signaling appears to be restricted to the recruitment of JAK3 [13]. By contrast, CD122 provides essential docking sites for at least two major downstream signaling mediators, the adaptor protein Shc and the transcription factor STAT5. CD122 is common to both the IL-2R and IL-15R, with each receptor having a unique a chain that defines receptor specificity (IL-2Ra and IL-15Ra, respectively). Unlike CD122, the role of CD25 appears to be confined to increasing binding affinity (KD *10 -9 -10 -11 M) and it is postulated that the short cytoplasmic domain is unlikely to contribute to signaling [13][14][15][16][17][18].Several lines of evidence suggest that IL-2 is essential for the homeostatic proliferation of Treg. For example, bone marrow chimera studies showed that IL-2 production by non-Treg is required for Treg maintenance [19]. In addition, treatment of mice with...

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Generalized autoimmune disease in interleukin‐2‐deficient mice is triggered by an uncontrolled activation and proliferation of CD4⁺ T cells

Cited by 398 publications

References 21 publications

Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango

Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango

Differential role of IL‐2R signaling for CD8⁺ T cell responses in acute and chronic viral infections

IL‐2Rβ links IL‐2R signaling with Foxp3 expression

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Generalized autoimmune disease in interleukin‐2‐deficient mice is triggered by an uncontrolled activation and proliferation of CD4+ T cells

Cited by 398 publications

References 21 publications

Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL‐)two to tango

Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL‐)two to tango

Differential role of IL‐2R signaling for CD8+ T cell responses in acute and chronic viral infections

IL‐2Rβ links IL‐2R signaling with Foxp3 expression

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Generalized autoimmune disease in interleukin‐2‐deficient mice is triggered by an uncontrolled activation and proliferation of CD4⁺ T cells

Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango

Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango

Differential role of IL‐2R signaling for CD8⁺ T cell responses in acute and chronic viral infections