1α, 25‐dihydroxyvitamin D3 acts via transforming growth factor‐β to up‐regulate expression of immunosuppressive CD73 on human CD4+ Foxp3– T cells. Issue 3 (13th September 2015)

• Record Type: Journal Article
• Authors: Mann, Elizabeth H.; Chambers, Emma S.; Chen, Yin‐Huai; Richards, David F.; Hawrylowicz, Catherine M.
• Is Part Of: Immunology. Volume 146:Issue 3(2015:Nov.)
• Page Start: 423
• Page End: 431
• Publication Date: 2015-09-13
• Subjects: Immunology -- Periodicals
• DOI: 10.1111/imm.12519
• Languages: English
• ISSNs: 0019-2805

Abstract

<abstract abstract-type="main" id="imm12519-abs-0001"> <title>Summary</title> <p>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)<sub>2</sub>D3) up‐regulates CD4<sup>+</sup> 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)<sub>2</sub>D3 on expression of the downstream ecto‐5′‐nucleotidase CD73 by human CD4 T cells, and components of the transforming growth factor‐<italic>β</italic> (TGF‐<italic>β</italic>) pathway, which have been implicated in the modulation of CD73 by murine T cells. At 10<sup>−8</sup> to 10<sup>−7</sup><sc>m</sc>, 1, 25(OH)<sub>2</sub>D3 significantly increased expression of CD73 on peripheral human CD4<sup>+</sup> T cells. Although 1, 25(OH)<sub>2</sub>D3 did not affect the mRNA expression of latent TGF‐<italic>β</italic><sub>1</sub>, 1, 25(OH)<sub>2</sub>D3 did up‐regulate expression of TGF‐<italic>β</italic>‐associated molecules [latency‐associated peptide (LAP), glycophorin A repetitions predominant (GARP), GP96, neuropilin‐1, thrombospondin‐1 and α<sub>v</sub> integrin] which is likely to have contributed to the observed enhancement in TGF‐<italic>β</italic> bioactivity. CD73 was highly co‐expressed with LAP and GARP following 1, 25(OH)<sub>2</sub>D3 treatment, but unexpectedly, each of these cell surface molecules was expressed primarily on CD4<sup>+</sup> Foxp3<sup>–</sup> T cells, rather than CD4<sup>+</sup> Foxp3<sup>+</sup> T cells. Notably, neutralization of TGF‐<italic>β</italic> significantly impaired 1, 25(OH)<sub>2</sub>D3‐mediated induction of CD73. Collectively, we show that 1, 25(OH)<sub>2</sub>D3 enhances expression of CD73 on CD4<sup>+</sup> Foxp3<sup>–</sup> T cells in a process that is at least partially TGF‐<italic>β</italic>‐dependent. These data reveal an additional contributing mechanism by which vitamin D may be protective in immune‐mediated disease.</p> </abstract>