Journal of Biological Chemistry
Volume 292, Issue 50, 15 December 2017, Pages 20657-20668
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Immunology
Hormonal vitamin D up-regulates tissue-specific PD-L1 and PD-L2 surface glycoprotein expression in humans but not mice

https://doi.org/10.1074/jbc.M117.793885 Get rights and content
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PD-L1 (programmed death ligand 1) and PD-L2 are cell-surface glycoproteins that interact with programmed death 1 (PD-1) on T cells to attenuate inflammation. PD-1 signaling has attracted intense interest for its role in a pathophysiological context: suppression of anti-tumor immunity. Similarly, vitamin D signaling has been increasingly investigated for its non-classical actions in stimulation of innate immunity and suppression of inflammatory responses. Here, we show that hormonal 1,25-dihydroxyvitamin D (1,25D) is a direct transcriptional inducer of the human genes encoding PD-L1 and PD-L2 through the vitamin D receptor, a ligand-regulated transcription factor. 1,25D stimulated transcription of the gene encoding PD-L1 in epithelial and myeloid cells, whereas the gene encoding the more tissue-restricted PD-L2 was regulated only in myeloid cells. We identified and characterized vitamin D response elements (VDREs) located in both genes and showed that 1,25D treatment induces cell-surface expression of PD-L1 in epithelial and myeloid cells. In co-culture experiments with primary human T cells, epithelial cells pretreated with 1,25D suppressed activation of CD4+ and CD8+ cells and inhibited inflammatory cytokine production in a manner that was abrogated by anti-PD-L1 blocking antibody. Consistent with previous observations of species-specific regulation of immunity by vitamin D, the VDREs are present in primate genes, but neither the VDREs nor the regulation by 1,25D is present in mice. These findings reinforce the physiological role of 1,25D in controlling inflammatory immune responses but may represent a double-edged sword, as they suggest that elevated vitamin D signaling in humans could suppress anti-tumor immunity.

gene expression
immunology
inflammation
steroid hormone receptor
vitamin D
anti-tumor immunity
checkpoint inhibitors
inflammatory T cell responses
vitamin D signaling

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This work was supported by grants from the Canadian Institutes of Health Research (MOP 106439) and Genome Quebec (to J. H. W.). The authors declare that they have no conflicts of interest with the contents of this article.

This article contains supplemental Table S1 and Figs. S1–S18.

1

Recipient of a postdoctoral fellowship from the Fonds de Recherche en Santé Québec.

2

Recipient of a studentship from the Fonds de Recherche en Santé Québec.