1α,25‐dihydroxyvitamin D3 in combination with transforming growth factor‐β increases the frequency of Foxp3+ regulatory T cells through preferential expansion and usage of interleukin‐2

• Published in: Immunology 2014-09, Vol.143 (1), p.52-60
• Main Authors: Chambers, Emma S., Suwannasaen, Duangchan, Mann, Elizabeth H., Urry, Zoe, Richards, David F., Lertmemongkolchai, Ganjana, Hawrylowicz, Catherine M.
• Format: Article
• Language: English
• Subjects: 1α,25‐dihydroxyvitamin D3; Cell Proliferation - drug effects; Cells, Cultured; Flow Cytometry; Forkhead Transcription Factors - immunology; Foxp3+ regulatory T cells; Humans; Interleukin-2 - immunology; interleukin‐2; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Original; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocyte Subsets - cytology; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - pharmacology; transforming growth factor‐β; Vitamin D - analogs & derivatives; Vitamin D - immunology; Vitamin D - pharmacology
• ISSN: 0019-2805; 1365-2567
• DOI: 10.1111/imm.12289

Summary A high prevalence of vitamin D insufficiency and deficiency exists worldwide, which is associated with an increased incidence and severity of a range of immune‐mediated diseases. This has resulted in considerable interest in the immunodulatory functions of vitamin D. The active form of vitamin D, 1α,25‐dihydroxyvitamin D3 [1,25(OH)2D3], has been shown to increase the frequency of Foxp3+ CD4+ T regulatory (Treg) cells when present at high concentrations or under strong T‐cell stimulation in culture. Supporting evidence exists in vivo for a positive association between serum 25(OH)D and Foxp3+ Treg cell numbers in humans. The aim of this work was to identify the cytokine milieu required in vitro to promote Foxp3+ Treg cells in cultures containing 1,25(OH)2D3 at more moderate concentrations (10−7 m). Stimulation of human CD4+ T cells with a combination of 1,25(OH)2D3 and transforming growth factor‐β (TGF‐β) greatly increased the frequency of Foxp3+ Treg cells, which is proposed to result from the preferential expansion of Foxp3+ Treg cells, as compared with the Foxp3− effector T cells, in culture. The differential effect on proliferation may result from enhanced availability and usage of interleukin‐2 by the Foxp3+ Treg cells compared with Foxp3− effector T cells. In summary, modulation of the cytokine environment to one high in TGF‐β in the presence of 1,25(OH)2D3 (10−7 m) significantly increased Foxp3+ Treg cell frequency. These data provide additional evidence for the important immunomodulatory properties of 1,25(OH)2D3 that exist and may help to control inflammatory diseases.