title: Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses.
abstract: 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the active form of vitamin D, exerts potent effects on several tissues including cells of the immune system, where it affects T cell activation, differentiation and migration. The circulating, inactive form of vitamin D, 25(OH)D(3), is generally used as an indication of vitamin D status. However, use of this precursor depends on its uptake by cells and subsequent conversion by the enzyme 25(OH)D(3)-1α-hydroxylase (CYP27B1) into active 1,25(OH)(2)D(3). Using human T cells, we show in this study that addition of inactive 25(OH)D(3) is sufficient to alter T cell responses only when dendritic cells (DCs) are present. Mechanistically, CYP27B1 is induced in DCs upon maturation with LPS or upon T cell contact, resulting in the generation and release of 1,25(OH)(2)D(3), which subsequently affects T cell responses. In most tissues, vitamin D binding protein acts as a carrier to enhance the use of vitamin D. However, we show that vitamin D binding protein modulates T cell responses by restricting the availability of inactive 25(OH)D(3) to DC. These data indicate that the level of free 25(OH)D(3) available to DCs determines the inflammatory/regulatory balance of ensuing T cell responses.
authors.affiliation: Medical Research Council Centre for Immune Regulation, School of Immunity and Infection, Institute of Biomedical Research, University of Birmingham College of Medical and Dental Sciences, Birmingham B15 2TT, United Kingdom.
authors.forename: Louisa E
authors.initials: LE
authors.lastname: Jeffery
authors.forename: Alice M
authors.initials: AM
authors.lastname: Wood
authors.forename: Omar S
authors.initials: OS
authors.lastname: Qureshi
authors.forename: Tie Zheng
authors.initials: TZ
authors.lastname: Hou
authors.forename: David
authors.initials: D
authors.lastname: Gardner
authors.forename: Zoe
authors.initials: Z
authors.lastname: Briggs
authors.forename: Satdip
authors.initials: S
authors.lastname: Kaur
authors.forename: Karim
authors.initials: K
authors.lastname: Raza
authors.forename: David M
authors.initials: DM
authors.lastname: Sansom
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000276:immunology / Q000378:metabolism*; D002112:Calcifediol / Q000276:immunology* / Q000378:metabolism; D002117:Calcitriol / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002112:Calcifediol