Normal Lymphoid Homeostasis and Lack of Lethal Autoimmunity in Mice Containing Mature T Cells with Severely Impaired IL-2 Receptors

Malek, Thomas R.; Porter, Brian; Codias, Elaine K.; Scibelli, Paul; Yu, Aixin

doi:10.4049/jimmunol.164.6.2905

Cited by 139 publications

(144 citation statements)

References 40 publications

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“…Malek and colleagues [24] showed that restoration of a thymic IL-2Rb signal curtailed the development of autoimmunity in il2rb -/-animals, despite loss of il2rb expression upon emigration to the periphery. Recently, these animals were found to have normal numbers of thymic and peripheral Foxp3 + Treg, which exhibit in vitro suppressive ability but fail to persist when transferred to another host.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, it is not clear whether the IL-2 signal is directly involved in Treg development, possibly by regulating Foxp3 expression, or whether it is only required for their maintenance in the periphery. Tg mice, which express a thymus-restricted il2rb transgene on an il2rb -/-background (referred to as il2rb -/-ThyTg), have shed some light on this issue [24,25]. These mice develop CD4 + CD25 + Treg and are protected from the development of autoimmunity, indicating that an IL-2R signal is required by nascent Treg as they develop in the thymus.…”

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confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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

2007

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“…Previous in vitro studies demonstrated that T cells from Tg Ϫ/Ϫ mice readily proliferated (ϳ50% of normal control mice) after stimulation by anti-CD3 (23,24). This proliferation was substantially inhibited by blocking costimulation through CD40 ligand and CD28, but unaffected by the addition of mAbs to IL-2 and ␥ c (24).…”

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confidence: 97%

“…Thymic targeted Tg wild-type IL-2R␤ expressed in IL-2R␤ Ϫ/Ϫ mice on the C57BL/6 genetic background (designated Tg Ϫ/Ϫ in this report) have been previously described (23,24). C57BL/6 and BALB/c mice were obtained from The Jackson Laboratory (Bar Harbor, ME).…”

Section: Micementioning

confidence: 99%

“…Our laboratory has developed such a mouse model by expressing IL-2R␤ as a transgene in the thymus of IL-2R␤ Ϫ/Ϫ mice (23,24). Peripheral T cells in these mice (designated transgenic (Tg) Ϫ/Ϫ ) remained nonresponsive to IL-2 and IL-15, yet Tg Ϫ/Ϫ mice did not exhibit autoimmunity and uncontrolled expansion of activated peripheral T cells (23,24). More recent studies demonstrated that autoimmunity was prevented in Tg Ϫ/Ϫ mice by restoring production of CD4 ϩ CD25 ϩ T regulatory cells (25).…”

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Efficient Induction of Primary and Secondary T Cell-Dependent Immune Responses In Vivo in the Absence of Functional IL-2 and IL-15 Receptors

Zhou²,

Marten³

et al. 2003

The Journal of Immunology

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IL-2 and IL-15 are thought to be important cytokines for T cell-dependent immune responses. Mice deficient in IL-2, IL-2Rα, and IL-2Rβ are each characterized by a rapid lethal autoimmune lymphoproliferative disorder that complicates their use in studies aimed at investigating the role of these cytokines and receptors for immune responses in vivo. We have previously characterized a novel transgenic (Tg) mouse on the IL-2Rβ−/− genetic background (Tg−/− mice) that lacks autoimmune disease but still contains peripheral T cells that are nonresponsive to IL-2 and IL-15. In the present study, these mice were used to investigate the extent by which IL-2 and IL-15 are essential for T cell immunity in vivo. Tg−/− mice generated near normal primary and secondary Ab responses to OVA, readily mounted first and second set allogeneic skin graft rejection responses, and developed primary and recall CD8 T cell responses to vaccinia virus. However, Tg−/− mice generated a slightly lower level of IgG2a Abs to OVA, exhibited a somewhat delayed first set skin graft rejection response with lower allo-specific CTL, and developed a significantly lower number of IFN-γ-producing vaccinia-specific CD8+ T cells. Thus, although T effector function is somewhat impaired, T cell immunity is largely functional in the absence of IL-2- and IL-15-induced signaling through IL-2Rβ.

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Control of T cell hyperactivation in IL-2-deficient mice by CD4+CD25- and CD4+CD25+ T cells: evidence for two distinct regulatory mechanisms

2001

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In IL‐2‐deficient mice, antigen‐activated CD4 T cells accumulate and cause lethal immune pathology. Wild‐type cells of hematopoietic origin present in the same animal are able to prevent this hyperactivation of T cells, but the mechanisms and cells controlling the IL‐2‐deficient cells are unknown. Here we show that IL‐2– CD4 cells with an ovalbumin‐specific transgenic TCR (IL‐2– OVAtg) undergo both clonal expansion and clonal contraction when transferred to euthymic recipients and challenged with antigen, but continuously expand in athymic hosts. Cotransfer of wild‐type CD4 T cells prevents the accumulation of IL‐2‐deficient cells. On the residual IL‐2– TCRtg cells CD69 and CD25 are up‐regulated, suggesting that activation per se is not suppressed and that the cells had received an IL‐2 signal. Since IL‐2 is able to restore the defective antigen‐induced cell death (AICD) of IL‐2‐deficient T cells in vitro, paracrine IL‐2 provided by the wild‐type CD4 cells may thus be able to allow clonal contraction of IL‐2‐deficient cells also in vivo. Interestingly however, regulatory CD4+CD25+ cells also efficiently contain the clone size of antigen‐stimulated IL‐2‐deficient T cells. Since CD4+CD25+ cells do not produce IL‐2, this suggests a mechanism of suppression distinct from paracrine IL‐2 delivery. In keeping with this, the residual IL‐2– TCRtg cells recovered after cotransfer of regulatory CD4+CD25+ cells do not show increased CD25 or CD69 expression, suggesting that they had not received paracrine IL‐2 and that clonal containment occurred at the level of initial activation rather than clonal contraction by AICD. IL‐2 deficiency therefore mayupset T cell homeostasis by two distinct mechanisms: the failure to program expanding T cells for apoptosis, and the failure to generate functional CD4+CD25+ regulatory cells.

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Normal Lymphoid Homeostasis and Lack of Lethal Autoimmunity in Mice Containing Mature T Cells with Severely Impaired IL-2 Receptors

Cited by 139 publications

References 40 publications

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

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

Efficient Induction of Primary and Secondary T Cell-Dependent Immune Responses In Vivo in the Absence of Functional IL-2 and IL-15 Receptors

Control of T cell hyperactivation in IL-2-deficient mice by CD4+CD25- and CD4+CD25+ T cells: evidence for two distinct regulatory mechanisms

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