Lei Guang-Sheng, Zhang Chen, Lee Chao-Hung
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
Infect Immun. 2015 Feb;83(2):572-82. doi: 10.1128/IAI.02686-14. Epub 2014 Nov 17.
Myeloid-derived suppressor cells (MDSCs) were recently found to accumulate in the lungs during Pneumocystis pneumonia (PcP). Adoptive transfer of these cells caused lung damage in recipient mice, suggesting that MDSC accumulation is a mechanism of pathogenesis in PcP. In this study, the phagocytic activity of alveolar macrophages (AMs) was found to decrease by 40% when they were incubated with MDSCs from Pneumocystis-infected mice compared to those incubated with Gr-1(+) cells from the bone marrow of uninfected mice. The expression of the PU.1 gene in AMs incubated with MDSCs also was decreased. This PU.1 downregulation was due mainly to decreased histone 3 acetylation and increased DNA methylation caused by MDSCs. MDSCs were found to express high levels of PD-L1, and alveolar macrophages (AMs) were found to express high levels of PD-1 during PcP. Furthermore, PD-1 expression in AMs from uninfected mice was increased by 18-fold when they were incubated with MDSCs compared to those incubated with Gr-1(+) cells from the bone marrow of uninfected mice. The adverse effects of MDSCs on AMs were diminished when the MDSCs were pretreated with anti-PD-L1 antibody, suggesting that MDSCs disable AMs through PD-1/PD-L1 ligation during PcP.
最近发现，肺孢子菌肺炎（PcP）期间骨髓来源的抑制细胞（MDSCs）会在肺部积聚。将这些细胞过继转移会导致受体小鼠出现肺损伤，这表明MDSC积聚是PcP发病机制之一。在本研究中，与用未感染小鼠骨髓中的Gr-1(+)细胞孵育的肺泡巨噬细胞（AMs）相比，用肺孢子菌感染小鼠的MDSCs孵育的AMs吞噬活性降低了40%。与MDSCs孵育的AMs中PU.1基因的表达也降低了。这种PU.1下调主要是由于MDSCs导致组蛋白3乙酰化减少和DNA甲基化增加。研究发现，在PcP期间MDSCs表达高水平的PD-L1，而肺泡巨噬细胞（AMs）表达高水平的PD-1。此外，与用未感染小鼠骨髓中的Gr-1(+)细胞孵育的AMs相比，用MDSCs孵育的未感染小鼠AMs中PD-1表达增加了18倍。用抗PD-L1抗体预处理MDSCs后，其对AMs的不利影响减弱，这表明在PcP期间MDSCs通过PD-1/PD-L1连接使AMs失能。
