title: 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.
abstract: 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.
authors.affiliation: MRC and Asthma-UK Centre for Allergic Mechanisms in Asthma, King's College London, London, UK.
authors.forename: Emma S
authors.initials: ES
authors.lastname: Chambers
authors.forename: Duangchan
authors.initials: D
authors.lastname: Suwannasaen
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Mann
authors.forename: Zoe
authors.initials: Z
authors.lastname: Urry
authors.forename: David F
authors.initials: DF
authors.lastname: Richards
authors.forename: Ganjana
authors.initials: G
authors.lastname: Lertmemongkolchai
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hawrylowicz
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508594:IL2 protein, human; D007376:Interleukin-2; D016212:Transforming Growth Factor beta; C118756:dihydroxy-vitamin D3; D014807:Vitamin D
keywords: 1α,25-dihydroxyvitamin D3; Foxp3+ regulatory T cells; interleukin-2; transforming growth factor-β