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Abstract
Programmed cell death ligand 1 (PD-L1) is widely expressed in a variety of human tumors, and inhibition of the PD-L1/PD-1 pathway represents one of the most promising therapy for many types of cancer. However, the physiological function of PD-L1 in tissue development is still unclear, although PD-L1 mRNA is abundant in many tissues. To address this puzzle, we investigated the function of PD-L1 in mammary gland development. Interestingly, we found that PD-L1 is enriched in protein C receptor (Procr)-expressing mammary stem cells (MaSCs), and PD-L1-expressing mammary basal cells (PD-L1+ basal cells) exhibit robust mammary regeneration capacity in transplantation assay. The lineage tracing experiment showed that PD-L1+ cells can differentiate into all lineages of mammary epithelium cells, suggesting that PD-L1+ basal cells have the activities of MaSCs. Furthermore, PD-L1 deficiency significantly impairs mammary development and reduces mammary regeneration capacity of mammary basal cells, suggesting that PD-L1 is not only enriched in MaSCs but also improves activities of MaSCs. In summary, these results demonstrated that PD-L1 is enriched in MaSCs and promotes mammary gland development and regeneration. Mechanistically, our data indicated that PD-L1 expression is induced by continuous activation of Wnt/ß-catenin signaling. In conclusion, these results demonstrated that PD-L1 is a marker of MaSCs, and PD-L1 is essential for mammary development. Our study provides novel insight into the physiological functions of PD-L1 in tissue development.
Highlights
Programmed cell death ligand 1 (PD-L1 or B7-H1) is a member of the B7 immunoglobulin superfamily (Dong et al, 1999)
Programmed cell death ligand 1-CreERT2-2A-tdTomato (C57BL/6J) mice were generated as illustrated in this article in Figure 2, heterozygous mice (PD-L1+/−) were healthy and fertile, homozygous mice (PD-L1−/−, PDL1 deficiency) were fertile, but were more vulnerable to suffer from autoimmune disease, resembling the PD-L1-null mutant mice reported before (Dong et al, 2004); Rosa26mTmG mice were purchased from the Jackson Laboratory
PD-L1 mRNA is abundant in many tissues, PD-L1 protein is restricted to immune cells and activated vascular endothelial cells for unknown reasons
Summary
Programmed cell death ligand 1 (PD-L1 or B7-H1) is a member of the B7 immunoglobulin superfamily (Dong et al, 1999). PD-L1 is known to be expressed on tumor cells and/or tumor infiltration immune cells, and its interaction with PD-1 expressed on activated T cells inhibits the T cell responses against the tumor, enabling tumor immune evasion (Dong et al, 2002; Chen, 2004; Zou and Chen, 2008; Pardoll, 2012; Kamphorst et al, 2017). The PD-L1 protein is only constitutively expressed on immune cells (Dong et al, 1999, 2019; Freeman et al, 2000; Curiel et al, 2003; Latchman et al, 2004; Saudemont et al, 2005; Terme et al, 2012; Iraolagoitia et al, 2016; Hartley et al, 2018) and is inducibly expressed in activated vascular endothelial cells (Mazanet and Hughes, 2002), mesenchymal stem cells (Augello et al, 2005), and cultured bone marrow-derived mast cells (Nakae et al, 2006). Little is known about the physiological function of PD-L1 in organ development and tissue regeneration
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