Department of Pathology, Microbiology, and Immunology, University of Nebraska Medical Center, 985900 Nebraska Medical Center, Omaha, NE 68198-5900, United States.
J Leukoc Biol. 2024 Mar 29;115(4):620-632. doi: 10.1093/jleuko/qiad158.
Myeloid-derived suppressor cells (MDSCs) are pathologically activated immature myeloid cells with immunosuppressive activity that expand during chronic inflammation, such as cancer and prosthetic joint infection (PJI). Myeloid-derived suppressor cells can be broadly separated into 2 populations based on surface marker expression and function: monocytic myeloid-derived suppressor cells (M-MDSCs) and granulocytic myeloid-derived suppressor cells (G-MDSCs). Granulocytic myeloid-derived suppressor cells are the most abundant leukocyte infiltrate during PJI; however, how this population is maintained in vivo and cellular heterogeneity is currently unknown. In this study, we identified a previously unknown population of Ly6G+Ly6C+F4/80+MHCII+ MDSCs during PJI that displayed immunosuppressive properties ex vivo. We leveraged F4/80 and MHCII expression by these cells for further characterization using cellular indexing of transcriptomes and epitopes by sequencing, which revealed a distinct transcriptomic signature of this population. F4/80+MHCII+ MDSCs displayed gene signatures resembling G-MDSCs, neutrophils, and monocytes but had significantly increased expression of pathways involved in cytokine response/production, inflammatory cell death, and mononuclear cell differentiation. To determine whether F4/80+MHCII+ MDSCs represented an alternate phenotypic state of G-MDSCs, Ly6G+Ly6C+F4/80-MHCII- G-MDSCs from CD45.1 mice were adoptively transferred into CD45.2 recipients using a mouse model of PJI. A small percentage of transferred G-MDSCs acquired F4/80 and MHCII expression in vivo, suggesting some degree of plasticity in this population. Collectively, these results demonstrate a previously unappreciated phenotype of F4/80+MHCII+ MDSCs during PJI, revealing that a granulocytic-to-monocytic transition can occur during biofilm infection.
髓源性抑制细胞（MDSCs）是具有免疫抑制活性的病理性激活的未成熟髓系细胞，在慢性炎症（如癌症和人工关节感染（PJI））期间扩增。髓源性抑制细胞可以根据表面标志物表达和功能广泛分为 2 种群体：单核细胞来源的髓源性抑制细胞（M-MDSCs）和粒细胞来源的髓源性抑制细胞（G-MDSCs）。粒细胞来源的髓源性抑制细胞是 PJI 期间最丰富的白细胞浸润；然而，该群体如何在体内维持以及细胞异质性目前尚不清楚。在这项研究中，我们在 PJI 期间鉴定了一种以前未知的 Ly6G+Ly6C+F4/80+MHCII+ MDSC 群体，该群体在体外表现出免疫抑制特性。我们利用这些细胞的 F4/80 和 MHCII 表达，通过转录组和表位的细胞索引测序进行进一步表征，揭示了该群体的独特转录组特征。F4/80+MHCII+ MDSC 显示出与 G-MDSC、中性粒细胞和单核细胞相似的基因特征，但与细胞因子反应/产生、炎症细胞死亡和单核细胞分化相关的途径的表达显著增加。为了确定 F4/80+MHCII+ MDSC 是否代表 G-MDSC 的另一种表型状态，我们使用 PJI 小鼠模型将 Ly6G+Ly6C+F4/80-MHCII-G-MDSC 从 CD45.1 小鼠中过继转移到 CD45.2 受体中。一小部分转移的 G-MDSC 在体内获得了 F4/80 和 MHCII 的表达，表明该群体具有一定程度的可塑性。总之，这些结果表明在 PJI 期间存在以前未被认识到的 F4/80+MHCII+ MDSC 表型，揭示了在生物膜感染过程中可能发生粒细胞向单核细胞的转化。
