Tolerance, not immunity, crucially depends on IL-2

Malek, Thomas R.; Bayer, Allison L.

doi:10.1038/nri1435

Cited by 739 publications

(610 citation statements)

References 109 publications

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“…Despite the functional significance of CD25 and IL-2 signalling in naturally occurring Treg [11][12][13][14][15][16], the data presented here document deletion of diabetogenic cells by the fusion protein. Targeting cells that express the IL-2 receptor decreased the responsiveness to alloantigens in vitro, impaired adoptive transfer of the disease into NOD SCID mice and antagonised cyclophosphamide-induced destructive insulitis.…”

Section: Discussionmentioning

confidence: 68%

“…IL-2 is an attractive target of immunotherapy as an important constituent of immune activation [9,10]. Subsets of naturally occurring Treg that emerge from the thymus as a distinct cell type [11,12] are not only characterised by expression of high levels of the high-affinity α chain of the IL-2 receptor (CD25) [13], but also depend on IL-2 for their expansion and function [14,15]. The implications and pleiotropic functions of IL-2 in autoimmune disorders have been extensively debated.…”

Section: Introductionmentioning

confidence: 99%

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Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Yarkoni¹,

Kaminitz

Sagiv³

et al. 2009

Diabetologia

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Aims/hypothesis Interruption of IL-2 signalling is an attractive therapeutic target in autoimmune disorders. In this study we evaluated the effect of a fusion protein composed of IL-2 and caspase-3 (IL2-cas) on NOD mice, as compared with disease induction by cyclophosphamide. Methods IL2-cas was assessed in NOD mice at various ages and in conjunction with cyclophosphamide administration. The effect of IL2-cas on diabetogenic cells was evaluated in adoptive transfer experiments and in cell suspension in vitro. Results IL2-cas induced apoptosis in T cells expressing the α chain of the IL-2 receptor (cluster of differentiation [CD] 25) in vitro, with superior survival of T cells expressing CD4 and forkhead box P3 (FOXP3). The fusion protein decreased mixed lymphocyte reactivity, and pretreatment with IL2-cas decreased the efficacy of adoptive transfer of diabetes into NOD severe combined immunodeficiency mice. Administration of one dose of IL2-cas decreased the incidence of diabetes in NOD mice, showing a superior beneficial effect when administered at young age, and effectively blocked induction of hyperglycaemia by cyclophosphamide, reducing the severity of islet inflammation. Administration of IL2-cas caused an acute increase in CD25 -FOXP3 + T cells in the lymph nodes, pancreas and thymus in NOD mice, with similar effects in wild-type mice. Administration of IL2-cas after onset of hyperglycaemia resulted in superior survival. Conclusions/interpretation Targeted elimination of cells expressing the IL-2 receptor by this fusion protein disrupts the autoimmune pathogenesis in prediabetic and diabetic NOD mice, despite depletion of CD25 + regulatory T cells. Furthermore, this particular fusion protein is permissive to the development of FOXP3 + T cells that might contribute to protracted protection from the progression of insulitis and overt hyperglycaemia.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Yarkoni¹,

Kaminitz

Sagiv³

et al. 2009

Diabetologia

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“…For a long time, CD25 was merely regarded as a surrogate Treg marker without functional relevance. Only recently has it become clear that IL-2 plays an essential role for Treg development and homeostasis (reviewed in [18]). IL-2 was originally identified as an important T cell growth factor in vitro [19].…”

Section: Il-2 Is Essential For Treg Homeostasismentioning

confidence: 99%

“…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]. IL-2 mainly plays a role for the peripheral expansion and maintenance of Treg [1,18,31] rather than their thymic generation since Treg develop in IL-2-deficient mice [16,28].…”

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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“…This observation might indicate that c c -dependent cytokines other than IL-7 are involved in the homeostasis of naive T cells. Alternatively, these results might have been influenced by the propensity of c c -deficient mice to develop an inflammatory syndrome (secondary to generalized T cell activation resulting from an absence of regulatory T cells [22]). Our knowledge of the biological roles played by c c cytokines he maintenance of naive T cells remains incomplete.…”

Section: Introductionmentioning

confidence: 99%

γ_c cytokines provide multiple homeostatic signals to naive CD4⁺ T cells

et al. 2007

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Cytokines signaling through receptors sharing the common γ chain (γc), including IL‐2, IL‐4, IL‐7, IL‐9, IL‐15 and IL‐21, are critical for the generation and peripheral homeostasis of B, T and NK cells. To identify unique or redundant roles for γc cytokines in naive CD4+ T cells, we compared monoclonal populations of CD4+ T cells from TCR‐Tg mice that were γ, γ, CD127–/– or CD122–/–. We found that γ naive CD4+ T cells failed to accumulate in the peripheral lymphoid organs and the few remaining cells were characterized by small size, decreased expression of MHC class I and enhanced apoptosis. By over‐expressing human Bcl‐2, peripheral naive CD4+ T cells that lack γc could be rescued. Bcl‐2+ γ CD4+ T cells demonstrated enhanced survival characteristics in vivo and in vitro, and could proliferate normally in vitro in response to antigen. Nevertheless, Bcl‐2+ γ CD4+ T cells remained small in size, and this phenotype was not corrected by enforced expression of an activated protein kinase B. We conclude that γc cytokines (primarily but not exclusively IL‐7) provide Bcl‐2‐dependent as well as Bcl‐2‐independent signals to maintain the phenotype and homeostasis of the peripheral naive CD4+ T cell pool.See accompanying commentary: http://dx.doi.org/10.1002/eji.200737721

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Tolerance, not immunity, crucially depends on IL-2

Cited by 739 publications

References 109 publications

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

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

γ_c cytokines provide multiple homeostatic signals to naive CD4⁺ T cells

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Tolerance, not immunity, crucially depends on IL-2

Cited by 739 publications

References 109 publications

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

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

γc cytokines provide multiple homeostatic signals to naive CD4+ T cells

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

γ_c cytokines provide multiple homeostatic signals to naive CD4⁺ T cells