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 2

TGF-β is not upregulated by vitamin D3 and dexamethasone treatment and does not play a role in IL-10–secreting Treg–mediated suppression of Th1 and Th2 cytokine production.

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TGF-β is not upregulated by vitamin D3 and dexamethasone treatment and d...
(A) CD4+ T cells were stimulated for 7 days with (T vit/dex) or without (T neutral) vitamin D3 and dexamethasone, as for Figure 1, and restimulated without drugs for 48 hours. TGF-β and IL-10 levels in culture supernatants were determined by ELISA. Mean data of 3 experiments are shown. (B) CD4+ T cells were cultured for two 7-day cycles with or without vitamin D3 and dexamethasone and then activated with PMA and ionomycin for 4 hours. PBMCs were cultured without or with PMA and ionomycin for 4 hours. TGF-β and IL-10 mRNA were determined by real-time RT-PCR and expressed relative to unactivated PBMCs. A representative experiment of 4 is shown. (C) CD4+ T cell lines were cultured for 7 days with vitamin D3 and dexamethasone and then used in cocultures with fresh autologous T cells (1:4 ratio) and irradiated APCs. Day 3 supernatants were assessed for IFN-γ and IL-13 content. Mean data from 4 experiments is shown. *P < 0.05 using 2-tailed Student’s t test.