Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 42, Issue 10, Pages 2697-2708Publisher
WILEY
DOI: 10.1002/eji.201242370
Keywords
1a; 25-Dihydroxyvitamin D3; Asthma; Immune regulation; Regulatory T cells
Categories
Funding
- MRC
- EURO-Thymaide
- MRC British Thoracic Society/Morriston Davies Trust
- British Lung Foundation Fellowship
- Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre
- BMA James Trust Fellowship
- MRC, UK
- MRC [MC_U117565642] Funding Source: UKRI
- Asthma UK [MRC-AsthmaUKCentre] Funding Source: researchfish
- Medical Research Council [MC_U117565642, G1000758, G1000758B] Funding Source: researchfish
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1a,25-Dihydroxyvitamin D3 (1a25VitD3) has potent immunomodulatory properties. We have previously demonstrated that 1a25VitD3 promotes human and murine IL-10-secreting CD4+ T cells. Because of the clinical relevance of this observation, we characterized these cells further and investigated their relationship with Foxp3+ regulatory T (Treg) cells. 1a25VitD3 increased the frequency of both Foxp3+ and IL-10+ CD4+T cells in vitro. However, Foxp3 was increased at high concentrations of 1a25VitD3 and IL-10 at more moderate levels, with little coexpression of these molecules. The Foxp3+ and IL-10+ T-cell populations showed comparable suppressive activity. We demonstrate that the enhancement of Foxp3 expression by 1a25VitD3 is impaired by IL-10. 1a25VitD3 enables the selective expansion of Foxp3+ Treg cells over their Foxp3- T-cell counterparts. Equally, 1a25VitD3 maintains Foxp3+ expression by sorted populations of human and murine Treg cells upon in vitro culture. A positive in vivo correlation between vitamin D status and CD4+Foxp3+ T cells in the airways was observed in a severe pediatric asthma cohort, supporting the in vitro observations. In summary, we provide evidence that 1a25VitD3 enhances the frequency of both IL-10+ and Foxp3+ Treg cells. In a translational setting, these data suggest that 1a25VitD3, over a broad concentration range, will be effective in enhancing the frequency of Treg cells.
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