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.
View: Text | PDF
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

×

Figure 4

Enhancement of glucocorticoid-induced IL-10 synthesis by T cells from SR asthma patients with vitamin D3 and pretreatment with IL-10.

Options: View larger image (or click on image) Download as PowerPoint
Enhancement of glucocorticoid-induced IL-10 synthesis by T cells from SR...
(A) CD4+ T cells from SS (n = 4) and GR (n = 8) asthma patients were cultured with anti-CD3, APCs, IL-2, IL-4, and the indicated combinations of 10–7 M dexamethasone and 5 × 10–7 M vitamin D3 for 7 days. Cells were recultured at 1 × 106 cells/ml with anti-CD3 and IL-2 alone, and 48-hour culture supernatants were assayed for IL-10 content by ELISA. One patient was tested 2 different times at an interval of 1 year. (B) CD4+ T cells from SS (n = 4) and SR (n = 6) asthma patients were cultured with APCs overnight in medium or with 2 ng/ml IL-10, washed and cultured with anti-CD3, IL-2, IL-4, and the indicated concentrations of dexamethasone, 5 × 10–7 M vitamin D3, or 10–7M dexamethasone plus vitamin D3 for 7 days. Cells were recultured with anti-CD3 and IL-2 alone and 48-hour culture supernatants assayed by ELISA. *P < 0.05; **P < 0.01 using 2-tailed Student’s t test.