Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils.

Somatic mutations commonly occur in hematopoietic stem cells (HSCs). Some mutant clones outgrow through clonal hematopoiesis (CH) and produce mutated immune progenies shaping host immunity. Individuals with CH are asymptomatic but have an increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Using genetic engineering of human HSCs (hHSCs) and transplantation in immunodeficient mice, we describe how a commonly mutated gene in CH, TET2, affects human neutrophil development and function. TET2 loss in hHSCs produce a distinct neutrophil heterogeneity in bone marrow and peripheral tissues by increasing the repopulating capacity of neutrophil progenitors and giving rise to low granule neutrophils. Human neutrophils that inherited TET2 mutations mount exacerbated inflammatory responses and have more condensed chromatin, which correlates with compact neutrophil extracellular trap (NET) production. We expose here physiological abnormalities that may inform future strategies to detect TET2-CH and prevent NET-mediated pathologies associated with CH.体细胞突变常发生于造血干细胞（hematopoietic stem cells, HSCs）中。部分突变克隆可通过克隆性造血（clonal hematopoiesis, CH）获得克隆性增殖优势，并产生携带突变的免疫子代细胞，进而重塑宿主免疫状态。携带CH的个体通常无明显临床症状，但罹患白血病、心血管与肺部炎症性疾病以及重症感染的风险显著升高。本研究通过对人类造血干细胞（human HSCs, hHSCs）实施基因工程改造并将其移植至免疫缺陷小鼠体内，阐明了CH中常见突变基因TET2对人类中性粒细胞发育与功能的调控机制。在hHSCs中缺失TET2，可通过增强中性粒细胞祖细胞的重建造血能力，并诱导产生低颗粒中性粒细胞，在骨髓与外周组织中形成独特的中性粒细胞异质性。携带TET2突变的人类中性粒细胞会呈现加剧的炎症应答，且染色质浓缩程度更高，这与更致密的中性粒细胞胞外陷阱（neutrophil extracellular trap, NET）形成密切相关。本研究揭示的上述生理异常，可为未来开发TET2-CH的检测策略，以及预防与CH相关的NET介导性病理提供理论依据。