Both integrated and differential regulation of components of the IL-2/IL-2 receptor system

Kim, Hyoung‐Pyo; Imbert, Jean; Leonard, Warren J.

doi:10.1016/j.cytogfr.2006.07.003

Cited by 283 publications

(291 citation statements)

References 155 publications

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“…4C); the effect was greater on the latter cells. Consistent with TSLP-induced IL-2R␣ expression, which increases high-affinity IL-2R expression and responsiveness of cells to low concentrations of IL-2 (21,22), TSLP increased IL-2-induced proliferation of CD4 ϩ T cells even at low concentrations of IL-2 (Fig. 4D).…”

Section: Tslp Elevates Sensitivity Of Cd4 ϩ T Cells To Low Dose Of Il-2supporting

confidence: 63%

Cutting Edge: Direct Action of Thymic Stromal Lymphopoietin on Activated Human CD4+ T Cells

Rochman

Watanabe

Arima

et al. 2007

The Journal of Immunology

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Thymic stromal lymphopoietin (TSLP) is a cytokine that promotes CD4+ T cell homeostasis and contributes to allergic and inflammatory responses. TSLP can act directly on mouse CD4+ T cells, but in humans, the available data have indicated that TSLP receptors are not expressed on CD4+ T cells and that TSLP instead activates dendritic cells, which in turn promote the proliferation and differentiation of CD4+ T cells. We now unexpectedly demonstrate the presence of TSLP receptors on activated human CD4+ T cells. Strikingly, whereas freshly isolated peripheral blood human T cells show little if any response to TSLP, TCR stimulation allows a potent response to this cytokine. Moreover, TSLP increases the sensitivity of human CD4+ T cells to low doses of IL-2, augmenting responsiveness of these cells to TCR engagement. Our results establish that human CD4+ T cells are direct targets for TSLP.

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Section: Tslp Elevates Sensitivity Of Cd4 ϩ T Cells To Low Dose Of Il-2supporting

confidence: 63%

Cutting Edge: Direct Action of Thymic Stromal Lymphopoietin on Activated Human CD4+ T Cells

Rochman

Watanabe

Arima

et al. 2007

The Journal of Immunology

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173

162

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“…Initially IL-2 was characterized as a T cell growth factor, yet genetic ablation of either the ligand (IL-2) or the receptor chains (CD25, CD122) resulted in autoimmunity rather than immunodeficiency [31]. Thus IL-2R signaling plays a significant role in immune regulation and maintenance of tolerance.…”

Section: Discussionmentioning

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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“…It is well-known that NF-kB is a key transcription factor involved in IL-2R chain expression in T cells and, more in general, in T cell activation and proliferation (38)(39)(40)(41). Using PHAactivated PBLs, we could detect the expression of NF-kB1 and NF-kB2, but not of RelA, RelB, or cRel (Fig.…”

Section: Pkc« and Il-2r Expressionmentioning

confidence: 81%

Protein Kinase Cε Regulates Proliferation and Cell Sensitivity to TGF-1β of CD4+ T Lymphocytes: Implications for Hashimoto Thyroiditis

Mirandola

Gobbi

Masselli

et al. 2011

The Journal of Immunology

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We have studied the functional role of protein kinase Cε (PKCε) in the control of human CD4+ T cell proliferation and in their response to TGF-1β. We demonstrate that PKCε sustains CD4+ T cell proliferation triggered in vitro by CD3 stimulation. Transient knockdown of PKCε expression decreases IL-2R chain transcription, and consequently cell surface expression levels of CD25. PKCε silencing in CD4 T cells potentiates the inhibitory effects of TGF-1β, whereas in contrast, the forced expression of PKCε virtually abrogates the inhibitory effects of TGF-1β. Being that PKCε is therefore implicated in the response of CD4 T cells to both CD3-mediated proliferative stimuli and TGF-1β antiproliferative signals, we studied it in Hashimoto thyroiditis (HT), a pathology characterized by abnormal lymphocyte proliferation and activation. When we analyzed CD4 T cells from HT patients, we found a significant increase of PKCε expression, accounting for their enhanced survival, proliferation, and decreased sensitivity to TGF-1β. The increased expression of PKCε in CD4+ T cells of HT patients, which is described for the first time, to our knowledge, in this article, viewed in the perspective of the physiological role of PKCε in normal Th lymphocytes, adds knowledge to the molecular pathophysiology of HT and creates potentially new pharmacological targets for the therapy of this disease.

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Both integrated and differential regulation of components of the IL-2/IL-2 receptor system

Cited by 283 publications

References 155 publications

Cutting Edge: Direct Action of Thymic Stromal Lymphopoietin on Activated Human CD4+ T Cells

Cutting Edge: Direct Action of Thymic Stromal Lymphopoietin on Activated Human CD4+ T Cells

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

Protein Kinase Cε Regulates Proliferation and Cell Sensitivity to TGF-1β of CD4+ T Lymphocytes: Implications for Hashimoto Thyroiditis

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