ABSTRACT

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells with potent immunosuppressive functions, which can inhibit the activation of immune responses under a steady-state condition and pathological conditions. We performed transcriptomic profiling of circulating CD33⁺HLA-DR⁺ myeloid antigen-presenting cells (APCs) and CD33⁺HLA-DR^– myeloid cells (potentially MDSCs) in healthy individuals. We sorted both subpopulations from peripheral blood mononuclear cells (PBMCs) of 10 healthy donors and performed RNA sequencing (RNA-Seq). We found that several signaling pathways associated with the positive regulation of immune responses, such as antigen presentation/processing, FcγR-mediated phagocytosis and immune cell trafficking, phosphoinositide 3-kinase (PI3K)/Akt signaling, DC maturation, triggering receptor expressed on myeloid cells 1 (TREM1) signaling, nuclear factor of activated T cells (NFAT) and IL-8 signaling were downregulated in CD33⁺HLA-DR^– myeloid cells. In contrast, pathways implicated in tumor suppression and anti-inflammation, including peroxisome proliferator-activated receptor (PPAR) and phosphatase and tensin homolog (PTEN), were upregulated in CD33⁺HLA-DR^– myeloid cells. These data indicate that PPAR/PTEN axis could be upregulated in myeloid cells to keep the immune system in check in normal physiological conditions. Our data reveal some of the molecular and functional differences between CD33⁺HLA-DR⁺ APCs and CD33⁺HLA-DR^– myeloid cells in a steady-state condition, reflecting the potential suppressive function of CD33⁺HLA-DR^– myeloid cells to maintain immune tolerance. For future studies, the same methodological approach could be applied to perform transcriptomic profiling of myeloid subsets in pathological conditions.

摘要

髓源性抑制细胞 (MDSCs) 是具有强大免疫抑制功能的异质细胞群，可在稳态条件和病理条件下抑制免疫反应的激活。我们对循环 CD33 ⁺ HLA-DR ⁺髓样抗原呈递细胞 (APC) 和 CD33 ⁺ HLA-DR进行了转录组分析^–健康个体的骨髓细胞（可能是 MDSC）。我们从 10 名健康供体的外周血单个核细胞 (PBMC) 中分选了两个亚群，并进行了 RNA 测序 (RNA-Seq)。我们发现几种信号通路与免疫反应的正向调节相关，例如抗原呈递/加工、FcγR 介导的吞噬作用和免疫细胞运输、磷酸肌醇 3-激酶 (PI3K)/Akt 信号通路、DC 成熟、触发骨髓表达的受体细胞 1 (TREM1) 信号传导、活化 T 细胞的核因子 (NFAT) 和 IL-8 信号传导在 CD33 ⁺ HLA-DR中下调^–髓细胞。相比之下，与肿瘤抑制和抗炎有关的途径，包括过氧化物酶体增殖物激活受体 (PPAR) 和磷酸酶和张力蛋白同源物 (PTEN)，在 CD33 ⁺ HLA-DR ^-骨髓细胞中上调。这些数据表明 PPAR/PTEN 轴可以在骨髓细胞中上调，以在正常生理条件下保持免疫系统受到检查。^{我们的数据揭示了 CD33 +} HLA-DR ⁺ APC 和 CD33 ⁺ HLA-DR ^–处于稳态条件下的骨髓细胞之间的一些分子和功能差异，反映了 CD33 ⁺ HLA-DR的潜在抑制功能^–髓细胞维持免疫耐受。对于未来的研究，可以应用相同的方法学方法对病理条件下的骨髓亚群进行转录组分析。