Reversing the defective induction of IL-10–secreting regulatory T cells in glucocorticoid-resistant asthma patients
Emmanuel Xystrakis, … , Christopher Corrigan, Catherine M. Hawrylowicz
Emmanuel Xystrakis, … , Christopher Corrigan, Catherine M. Hawrylowicz
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):146-155. https://doi.org/10.1172/JCI21759.
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Research Article Immunology

Reversing the defective induction of IL-10–secreting regulatory T cells in glucocorticoid-resistant asthma patients

Abstract

We previously reported that human CD4+ Tregs secrete high levels of IL-10 when stimulated in the presence of dexamethasone and calcitriol (vitamin D3). We now show that following stimulation by allergen, IL-10–secreting Tregs inhibit cytokine secretion by allergen-specific Th2 cells in an IL-10–dependent manner. A proportion of patients with severe asthma fail to demonstrate clinical improvement upon glucocorticoid therapy, and their asthma is characterized as glucocorticoid resistant (SR, abbreviation derived from “steroid resistant”). Dexamethasone does not enhance secretion of IL-10 by their CD4+ T cells. Addition of vitamin D3 with dexamethasone to cultures of SR CD4+ T cells enhanced IL-10 synthesis to levels observed in cells from glucocorticoid-sensitive patients cultured with dexamethasone alone. Furthermore, pretreatment with IL-10 fully restored IL-10 synthesis in these cells in response to dexamethasone. Vitamin D3 significantly overcame the inhibition of glucocorticoid-receptor expression by dexamethasone while IL-10 upregulated glucocorticoid-receptor expression by CD4+ T cells, suggesting potential mechanisms whereby these treatments may overcome poor glucocorticoid responsiveness. We show here that administration of vitamin D3 to healthy individuals and SR asthmatic patients enhanced subsequent responsiveness to dexamethasone for induction of IL-10. This strongly suggests that vitamin D3 could potentially increase the therapeutic response to glucocorticoids in SR patients.

Authors

Emmanuel Xystrakis, Siddharth Kusumakar, Sandra Boswell, Emma Peek, Zoë Urry, David F. Richards, Tonye Adikibi, Carol Pridgeon, Margaret Dallman, Tuck-Kay Loke, Douglas S. Robinson, Franck J. Barrat, Anne O’Garra, Paul Lavender, Tak H. Lee, Christopher Corrigan, Catherine M. Hawrylowicz

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Figure 1

Polyclonal activation of human CD4+ T cells in the presence of dexamethasone plus vitamin D3 induces IL-10 expression, which does not correlate with expression of the transcription factor Foxp3.

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Polyclonal activation of human CD4+ T cells in the presence of dexametha...
(A) CD4+ T cells from an SS asthma patient were cultured with APCs, anti-CD3, IL-2, and IL-4 alone (medium) or together with 10–7 M Vitamin D3 and 10–7 M dexamethasone (vit/dex). Cells were restimulated at 7 days with PMA and ionomycin for 4 hours, and coexpression of IL-10 with IL-2, IL-4, IFN-γ, or GM-CSF was analyzed by flow cytometry. Data are representative of 5 experiments. (B) Real-time RT-PCR was performed on PBMCs, freshly isolated CD4+CD25– and CD4+CD25+ T cells, and IL-10–secreting Tregs harvested after 14 days in culture to compare expression of Foxp3 and IL-10. Data are representative of 3 experiments. HPRT, hypoxanthine-guanine phosphoribosyl transferase.