Mechanisms of asthma and allergic inflammation
Fluticasone propionate increases CD4+CD25+ T regulatory cell suppression of allergen-stimulated CD4+CD25 T cells by an IL-10–dependent mechanism

https://doi.org/10.1016/j.jaci.2004.04.048Get rights and content

Abstract

Background

Corticosteroids are the most effective anti-inflammatory therapy for allergic diseases, and these drugs inhibit TH2 T-cell activation. We previously reported that CD4+CD25+ T cells from atopic donors suppressed allergen-stimulated T cells less than those from nonatopic donors.

Objective

We sought to determine the effect of fluticasone propionate (FP) on allergen-stimulated CD4+CD25 T cells and on the suppressive ability of CD4+CD25+ T cells.

Methods

CD4+CD25+ and CD4+CD25 T cells were separated from peripheral blood of atopic and nonatopic volunteers and cultured alone or mixed in the presence of allergen. Effects of FP were assessed by means of addition to cultures or preincubation with CD4+CD25+ T cells.

Results

FP inhibited allergen-stimulated proliferation of CD4+CD25 T cells in a dose-dependent manner. Preincubation of CD4+CD25+ T cells in FP increased subsequent suppressive activity of these cells in allergen-stimulated cultures with CD4+CD25 T cells. This effect was seen when cells were obtained from both nonatopic and atopic donors but was less for cells obtained from atopic individuals. Prior exposure of CD4+CD25+ T cells to FP also increased subsequent IL-10 production by these cells when stimulated with allergen, and addition of anti-IL-10 antibody reversed the steroid-induced enhancement of suppression in mixed cultures.

Conclusion

Increased suppression by CD4+CD25+ T cells might play a role in anti-inflammatory effects of corticosteroids in asthma and allergic diseases.

Section snippets

Methods

Volunteers were recruited from among the staff of Imperial College London and by advertisement. The study was approved by the Ethics Committee of the Royal Brompton and Harefield Hospitals NHS Trust. Volunteers were assessed by questionnaire on allergic symptoms and skin prick tests (ALK, Horsholm, Denmark) and assigned to atopic (positive history and at least one positive skin prick test result of 3 mm or larger in diameter than that elicited by the negative control) or nonatopic (no history

Effect of FP on allergen-stimulated proliferation of CD4+CD25 T cells

Inhibitory effects of corticosteroids on T-cell proliferation are well described.11 However, there are no reports of inhibition of isolated CD4+CD25 T cells. We previously showed that these CD4+CD25 T cells, in the absence of regulatory CD4+CD25+ T cells, show increased proliferation to allergen stimulation when compared with unseparated PBMCs.17 First, we examined the effects of different concentrations of FP on allergen-stimulated proliferation of CD4+CD25 T cells from 6 atopic subjects.

Discussion

We have recently reported that the suppressive activity of CD4+CD25+ regulatory T cells in allergen-stimulated in vitro cultures is diminished when cells from atopic allergic donors are compared with those from nonatopic control subjects.17 Corticosteroids are the mainstay of anti-inflammatory treatment for asthma. We now report that the corticosteroid FP inhibited allergen-stimulated proliferation of CD4+CD25 T cells. Furthermore, preincubation with FP increased the suppressive activity of CD4

Acknowledgements

We thank Drs Malcolm Johnson, Ian Adcock, Anne O'Garra, Catherine Hawrylowicz, Clare Lloyd, Eleanor Ling, David Ahern, Carol Pridgeon, Margaret Dallman, Clare Notley, Mark Larche, and Barry Kay for discussions of the study and Justine Arbery, RGN, for help with volunteer recruitment.

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    Supported by a grant from GlaxoSmithKline. DN and DSR are supported by the Wellcome Trust, United Kingdom.

    Disclosure of potential conflict of interest: X. D. Nguyen and D. S. Robinson received support from GlaxoSmithKline for attendance at scientific meetings. D. S. Robinson has received support from GlaxoSmithKline for research on regulatory T cells and honoraria for educational speaking engagements and is on the Speakers' Bureau for GlaxoSmithKline, AstraZeneca, 3M, and Schering Plough.

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