Abstract
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.
Highlights
PD-L1 and PD-L2 are cell-surface glycoproteins that interact with programmed death 1 (PD-1) on T cells to attenuate inflammation
5 The abbreviations used are: Teff, effector T; Treg, regulatory T; cytotoxic T lymphocytes (CTLs), cytotoxic T lymphocyte; IBD, inflammatory bowel disease; antigen-presenting cells (APCs), antigen-presenting cell; HNSCC, head and neck squamous cell carcinoma; VD, vitamin D; VDR, vitamin D receptor; vitamin D response elements (VDREs), vitamin D response element; 1,25D, 1,25-dihydroxyvitamin D; qPCR, quantitative PCR; Ms, macrophages; dendritic cells (DCs), dendritic cell; ChIP-seq, ChIP followed by next-generation sequencing; TSS, transcription start site; H3K4me1, histone 3 lysine 4 monomethylation; H3K27ac, histone 3 lysine 27 acetylation; Pol II, polymerase II; eRNA, enhancer RNA; PBMC, peripheral blood mononuclear cell; CD, Crohn’s disease; IP, immunoprecipitation; rcf, relative centrifugal force; ZO-1, zonula occludens-1
The results presented here reveal that 1,25D acting through the VDR directly induces the transcription of the genes encoding PD-L1 and PD-L2 in human cell lines and primary cultures
Summary
Effector T; Treg, regulatory T; CTL, cytotoxic T lymphocyte; IBD, inflammatory bowel disease; APC, antigen-presenting cell; HNSCC, head and neck squamous cell carcinoma; VD, vitamin D; VDR, vitamin D receptor; VDRE, vitamin D response element; 1,25D, 1,25-dihydroxyvitamin D; qPCR, quantitative PCR; Ms, macrophages; DC, dendritic cell; ChIP-seq, ChIP followed by next-generation sequencing; TSS, transcription start site; H3K4me, histone 3 lysine 4 monomethylation; H3K27ac, histone 3 lysine 27 acetylation; Pol II, polymerase II; eRNA, enhancer RNA; PBMC, peripheral blood mononuclear cell; CD, Crohn’s disease; IP, immunoprecipitation; rcf, relative centrifugal force; ZO-1, zonula occludens-1. The induction of PD-L1 and PD-L2 expression is a mechanism accounting for the effects of VD signaling in T cell tolerance and is in accord with other studies providing evidence that it is protective against IBD [21, 27, 28]. This may prove to be a double-edged sword in terms of physiological versus potential pathophysiological actions of VD signaling, as Figure 1. Elevated 1,25D-induced PD-L1 expression may be detrimental to anti-tumor immunity
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