PD-L1 regulates inflammatory programs of macrophages from human pluripotent stem cells
Handi Cao, Yang Xiang, Shihui Zhang, Yiming Chao, Jilong Guo, Theo Aurich, Joshua W. K. Ho, Yuanhua Huang, Pentao Liu, Ryohichi Sugimura
Abstract
Programmed death ligand 1 (PD-L1) serves as a pivotal immune checkpoint in both the innate and adaptive immune systems. PD-L1 is expressed in macrophages in response to IFNγ. We examined whether PD-L1 might regulate macrophage development. We established PD-L1 KO ( CD274 -/- ) human pluripotent stem cells and differentiated them into macrophages and observed a 60% reduction in CD11B + CD45 + macrophages in CD274 -/- ; this was orthogonally verified, with the PD-L1 inhibitor BMS-1166 reducing macrophages to the same fold. Single-cell RNA sequencing further confirmed the down-regulation of the macrophage-defining transcription factors SPI1 and MAFB . Furthermore, CD274 -/- macrophages reduced the level of inflammatory signals such as NF-κB and TNF, and chemokine secretion of the CXCL and CCL families. Anti-inflammatory TGF-β was up-regulated. Finally, we identified that CD274 -/- macrophages significantly down-regulated interferon-stimulated genes despite the presence of IFNγ in the differentiation media. These data suggest that PD-L1 regulates inflammatory programs of macrophages from human pluripotent stem cells.