粒细胞髓源性抑制细胞(G-MDSC)在构成早期外周血主要部分的异基因造血干细胞移植(allo-HSCT)后显示快速恢复。虽然G-MDSCs通过多种机制介导免疫抑制,它们在特定条件下也可能促进炎症。
■在allo-HSCT后90天内,从82名患者中分离出G-MDSCs,并检查了它们与自体CD3+T细胞的相互作用。CFSE染色后通过流式细胞术评估T细胞增殖,而分化和干扰素-γ分泌使用趋化因子受体谱分析和ELISpot测定进行表征,分别。通过与K562细胞共培养评估NK细胞的细胞毒性。采用人源化小鼠中的aGVHD异种模型来研究人白细胞的体内作用。此外,通过RNA测序分析G-MDSC的转录改变以研究功能转变。
■G-MDSCs促进早期炎症,通过促进细胞因子分泌和T细胞增殖,以及它们向促炎性T辅助细胞亚群的分化。在第28天,具有较高数量的G-MDSC的患者表现出发展II-IV级aGvHD的风险增加。此外,在第28天时将G-MDSC从患者过继转移到人源化小鼠中加剧了aGvHD。然而,在第90天,G-MDSCs导致免疫抑制,以吲哚胺2,3-双加氧酶基因表达上调和白细胞介素-10分泌为特征,同时抑制T细胞增殖。此外,G-MDSC在第28天和第90天的转录分析显示1445个基因差异表达。这些基因与各种途径有关,揭示G-MDSCs移植后早期分化的分子特征。此外,与内质网应激相关的基因在无aGvHD患者中上调.通过G-MDSC获得免疫抑制功能可能取决于CXCL2和DERL1基因的激活。
■我们的发现揭示了在同种异体HSCT后的前90天内G-MDSC的免疫特性的改变。此外,第28天G-MDSC的数量可作为aGvHD发展的预测指标.
UNASSIGNED: Granulocytic myeloid-derived suppressor cells (G-MDSCs) show fast recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) constituting the major part of peripheral blood in the early phase. Although G-MDSCs mediate immune suppression through multiple mechanisms, they may also promote inflammation under specific conditions.
UNASSIGNED: G-MDSCs were isolated from 82 patients following allo-HSCT within 90 days after allo-HSCT, and their interactions with autologous CD3+ T-cells were examined. T-cell proliferation was assessed by flow cytometry following CFSE staining, while differentiation and interferon-γ secretion were characterized using chemokine receptor profiling and ELISpot assays, respectively. NK cell cytotoxicity was evaluated through co-culture with K562 cells. An aGVHD xenogeneic model in humanized mice was employed to study the in vivo effects of human leukocytes. Furthermore, transcriptional alterations in G-MDSCs were analyzed via RNA sequencing to investigate functional transitions.
UNASSIGNED: G-MDSCs promoted inflammation in the early-stage, by facilitating cytokine secretion and proliferation of T cells, as well as their differentiation into pro-inflammatory T helper subsets. At day 28, patients with a higher number of G-MDSCs exhibited an increased risk of developing grades II-IV aGvHD. Besides, adoptive transfer of G-MDSCs from patients at day 28 into humanized mice exacerbated aGvHD. However, at day 90, G-MDSCs led to immunosuppression, characterized by upregulated expression of indoleamine 2,3-dioxygenase gene and interleukin-10 secretion, coupled with the inhibition of T cell proliferation. Furthermore, transcriptional analysis of G-MDSCs at day 28 and day 90 revealed that 1445 genes were differentially expressed. These genes were associated with various pathways, revealing the molecular signatures of early post-transplant differentiation in G-MDSCs. In addition, genes linked to the endoplasmic reticulum stress were upregulated in patients without aGvHD. The acquisition of immunosuppressive function by G-MDSCs may depend on the activation of CXCL2 and DERL1 genes.
UNASSIGNED: Our findings revealed the alteration in the immune characteristics of G-MDSCs within the first 90 days post-allo-HSCT. Moreover, the quantity of G-MDSCs at day 28 may serve as a predictive indicator for the development of aGvHD.