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1 α ,25‐dihydroxyvitamin D3 acts via transforming growth factor‐ β to up‐regulate expression of immunosuppressive CD73 on human CD4 + Foxp3 – T cells
Author(s) -
Mann Elizabeth H.,
Chambers Emma S.,
Chen YinHuai,
Richards David F.,
Hawrylowicz Catherine M.
Publication year - 2015
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12519
Subject(s) - foxp3 , t cell , biology , adenosine , immune system , medicine , microbiology and biotechnology , chemistry , endocrinology , immunology
Summary 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‐ β 1 , 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 α v 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.