title: 1α,25-dihydroxyvitamin D3 acts via transforming growth factor-β to up-regulate expression of immunosuppressive CD73 on human CD4+ Foxp3- T cells.
abstract: Vitamin D deficiency is associated with increased incidence and severity of various immune-mediated diseases. Active vitamin D (1α,25-dihydroxyvitamin D3; 1,25(OH)2 D3) up-regulates CD4(+) T-cell expression of the purine ectonucleotidase CD39, a molecule that is associated with the generation of anti-inflammatory adenosine. Here we aimed to investigate the direct impact of 1,25(OH)2 D3 on expression of the downstream ecto-5'-nucleotidase CD73 by human CD4 T cells, and components of the transforming growth factor-β (TGF-β) pathway, which have been implicated in the modulation of CD73 by murine T cells. At 10(-8) to 10(-7) m, 1,25(OH)2 D3 significantly increased expression of CD73 on peripheral human CD4(+) T cells. Although 1,25(OH)2 D3 did not affect the mRNA expression of latent TGF-β1 , 1,25(OH)2 D3 did up-regulate expression of TGF-β-associated molecules [latency-associated peptide (LAP), glycophorin A repetitions predominant (GARP), GP96, neuropilin-1, thrombospondin-1 and αv integrin] which is likely to have contributed to the observed enhancement in TGF-β bioactivity. CD73 was highly co-expressed with LAP and GARP following 1,25(OH)2 D3 treatment, but unexpectedly, each of these cell surface molecules was expressed primarily on CD4(+) Foxp3(-) T cells, rather than CD4(+) Foxp3(+) T cells. Notably, neutralization of TGF-β significantly impaired 1,25(OH)2 D3-mediated induction of CD73. Collectively, we show that 1,25(OH)2 D3 enhances expression of CD73 on CD4(+) Foxp3(-) T cells in a process that is at least partially TGF-β-dependent. These data reveal an additional contributing mechanism by which vitamin D may be protective in immune-mediated disease.
authors.affiliation: MRC and Asthma-UK Centre for Allergic Mechanisms in Asthma, King's College London, London, UK.
authors.forename: Elizabeth H
authors.initials: EH
authors.lastname: Mann
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.affiliation: MRC and Asthma-UK Centre for Allergic Mechanisms in Asthma, King's College London, London, UK.
authors.forename: Yin-Huai
authors.initials: YH
authors.lastname: Chen
authors.affiliation: MRC and Asthma-UK Centre for Allergic Mechanisms in Asthma, King's College London, London, UK.
authors.forename: David F
authors.initials: DF
authors.lastname: Richards
authors.affiliation: MRC and Asthma-UK Centre for Allergic Mechanisms in Asthma, King's College London, London, UK.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Hawrylowicz
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D058851:GPI-Linked Proteins; C087215:LRRC32 protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D015720:5'-Nucleotidase; C548241:NT5E protein, human; D002117:Calcitriol
keywords: 1α,25-dihydroxyvitamin D3; CD73; Foxp3; transforming growth factor-β