Abstract：
Idiopathic severe aplastic anemia (SAA) is a disease of bone marrow failure caused by T-cell-induced destruction of hematopoietic stem and progenitor cells (HSPCs), however the mechanism remains unclear. We performed single-cell RNA sequencing of PBMCs and BMMCs from SAA patients and healthy donors and identified a CD8+ T cell subset with a tissue residency phenotype (Trm) in bone marrow that exhibit high IFN-γ and FasL expression and have a higher ability to induce apoptosis in HSPCs in vitro through FasL expression. CD8+ Trm cells were induced by IL-15 presented by IL-15Rα on monocytes, especially CD16+ monocytes, which were increased in SAA patients. CD16+ monocytes contributed to IL-15-induced CD38+CXCR6+ pre-Trm differentiation into CD8+ Trm cells, which can be inhibited by the CD38 inhibitor 78c. Our results demonstrate that IL-15-induced CD8+ Trm cells are pathogenic cells that mediate HSPC destruction in SAA patients and are therapeutic targets for future treatments.
摘要：
特发性重型再生障碍性贫血（SAA）是由T细胞诱导的造血干细胞和祖细胞（HSPC）破坏引起的骨髓衰竭疾病，然而，机制尚不清楚。我们对来自SAA患者和健康供体的PBMC和BMMCs进行了单细胞RNA测序，并鉴定了在骨髓中具有组织驻留表型（Trm）的CD8T细胞亚群，该细胞亚群表现出高IFN-γ和FasL表达，并且具有更高的能力通过FasL表达体外诱导HSPC的凋亡。IL-15Rα在单核细胞上呈递IL-15诱导CD8+Trm细胞，尤其是CD16+单核细胞,在SAA患者中增加。CD16+单核细胞有助于IL-15诱导的CD38+CXCR6+前Trm分化为CD8+Trm细胞，可以被CD38抑制剂78c抑制。我们的结果表明，IL-15诱导的CD8Trm细胞是介导SAA患者HSPC破坏的致病细胞，并且是未来治疗的治疗靶标。
