Bone marrow CD8 Trm cells induced by IL-15 and CD16 monocytes contribute to HSPC destruction in human severe aplastic anemia.

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 CD38CXCR6 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.