Interleukin-2 receptor (CD25) upregulation on human T-lymphocytes: sensitivity to immunosuppressants is defined by the mode of T-lymphocyte activation

Ryffel, Bernhard; Willcocks, Joanie L.; Brooks, Nathalie; Woerly, G.

doi:10.1016/0162-3109(95)00023-m

Cited by 14 publications

(7 citation statements)

References 22 publications

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“…Interestingly, we found that RAPA almost completely blocked IL-17 production at 10 ng/ml. This concentration of RAPA has also been reported by others to effectively inhibit the production of certain cytokines such as IL-2 and IL-10 18 19…”

Section: Discussionsupporting

confidence: 76%

Inhibitory effect of rapamycin and dexamethasone on production of IL-17 and IFN-γ in Vogt–Koyanagi–Harada patients

Yang

Wen

Liu³

et al. 2008

Br J Ophthalmol

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Section: Discussionsupporting

confidence: 76%

Inhibitory effect of rapamycin and dexamethasone on production of IL-17 and IFN-γ in Vogt–Koyanagi–Harada patients

Yang

Wen

Liu³

et al. 2008

Br J Ophthalmol

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“…In particular, protein kinase Cα and Cθ, and calcineurin, were established to be required for CD25 expression [12, 13, 14, 15]. On the one hand, our observation that cyclosporin A prevented CD25 appearance at the cell surface supported the dependence of CD25 expression on the calcineurin pathway.…”

Section: Discussionsupporting

confidence: 67%

Tuning of T Cell Clone Size and Activation Threshold by Control of CD25 Expression through Mitogen-Activated Protein Kinase Pathways

Bitegye

Hannier²,

Guérif³

et al. 2002

Int Arch Allergy Immunol

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Background: Following T cell receptor (TcR) engagement, CD25 expression is upregulated by T cells and controls their proliferation. It is not known how CD25 expression levels differentially influence T helper (Th) 1 and Th2 cell physiology. Method: CD25 upregulation, and other T cell functions, were studied in human Th1 and Th2 clones following stimulation with various stimuli. The effects of pharmacological substances were then evaluated to identify the signaling pathways controlling CD25 upregulation. Results: Upon TcR engagement, one Th2 clone was induced to express substantially more CD25 than a Th1 clone, although both clones downregulated CD3 with similar dose responses. It was also found that the amount of antigen needed to elicit proliferation and cytokine production was considerably lowered in the presence of interleukin-2 (IL-2) for the Th2 cells, while for the Th1 cells the threshold of activation was not modified by the presence of IL-2. It was then shown that PP2 and cyclosporin A strongly inhibited CD25 expression in both clones, while wortmannin and Ro-31-8220 had more limited effects. In contrast, mitogen-activated protein kinase (MAPK) inhibitors had strikingly different effects on CD25, blocking its expression in the Th2 cells, while augmenting it, or leaving it unaffected, in the Th1 cells. Conclusion: These unexpected observations suggested that in some T cells TcR-mediated activation of the MAPK pathways may inhibit CD25 expression rather than promoting it. Absence of this negative control mechanism may endow Th2 cells with a growth advantage over Th1 cells and their effector functions may be elicited at lower antigen doses.

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“…However, rapamycin has only a modest effect on the survival of peripheral T cells in vivo (29). In activated T cells, rapamycin has been reported to inhibit IL-2R upregulation and IL-2-dependent proliferation in some studies (26,(30)(31)(32) but not others (33)(34)(35). Recent work suggests that while some CD4-dependent immune responses are rapamycin sensitive (36,37), CD8 ϩ T cell function is largely rapamycin resistant (29,36,38,39).…”

Section: Discussionmentioning

confidence: 99%

The Pim kinases control rapamycin-resistant T cell survival and activation

Fox

Hammerman

Thompson

2005

The Journal of Experimental Medicine

169

164

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Although Pim-1 or Pim-2 can contribute to lymphoid transformation when overexpressed, the physiologic role of these kinases in the immune response is uncertain. We now report that T cells from Pim-1−/−Pim-2−/− animals display an unexpected sensitivity to the immunosuppressant rapamycin. Cytokine-induced Pim-1 and Pim-2 promote the rapamycin-resistant survival of lymphocytes. The endogenous function of the Pim kinases was not restricted to the regulation of cell survival. Like the rapamycin target TOR, the Pim kinases also contribute to the regulation of lymphocyte growth and proliferation. Although rapamycin has a minimal effect on wild-type T cell expansion in vitro and in vivo, it completely suppresses the response of Pim-1−/−Pim-2−/− cells. Thus, endogenous levels of the Pim kinases are required for T cells to mount an immune response in the presence of rapamycin. The existence of a rapamycin-insensitive pathway that regulates T cell growth and survival has important implications for understanding how rapamycin functions as an immunomodulatory drug and for the development of complementary immunotherapeutics.

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Interleukin-2 receptor (CD25) upregulation on human T-lymphocytes: sensitivity to immunosuppressants is defined by the mode of T-lymphocyte activation

Cited by 14 publications

References 22 publications

Inhibitory effect of rapamycin and dexamethasone on production of IL-17 and IFN-γ in Vogt–Koyanagi–Harada patients

Inhibitory effect of rapamycin and dexamethasone on production of IL-17 and IFN-γ in Vogt–Koyanagi–Harada patients

Tuning of T Cell Clone Size and Activation Threshold by Control of CD25 Expression through Mitogen-Activated Protein Kinase Pathways

The Pim kinases control rapamycin-resistant T cell survival and activation

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