Abstract：
Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients with pulmonary cGVHD in particular have a very poor prognosis. NK cells are the first reconstituted lymphocyte subset after allo-HSCT; however, the impact of reconstituted NK cells on cGVHD is unclear. Here, we found allogeneic recipients showed obvious pulmonary cGVHD. Surprisingly, deletion of reconstituted NK cells resulted in maximal relief of pulmonary cGVHD. Mechanistically, reconstituted NK cells with donor profiles modulated the pulmonary inflammatory microenvironment to trigger cGVHD. Reconstituted NK cells secreted IFN-γ and TNF-α to induce CXCL10 production by epithelial cells, which recruited macrophages and CD4+ T cells to the lungs. Then macrophages and CD4+ T cells were activated by the inflammatory microenvironment, thereby mediating lung injury. Through assessment of differences in cellular energy, we found that CD74+ NK cells with high mitochondrial potential and pro-inflammatory activity triggered pulmonary cGVHD. Furthermore, targeted elimination of CD74+ NK cells using the anti-CD74 antibody significantly alleviated pulmonary cGVHD but preserved the CD74- NK cells to exert graft-versus-leukemia (GVL) effects. Data from human samples corroborated our findings in mouse models. Collectively, our results reveal that reconstituted CD74+ NK cells trigger pulmonary cGVHD and suggest that administration of CD74 antibody was a potential therapeutic for patients with cGVHD.
摘要：
慢性移植物抗宿主病（cGVHD）是异基因造血干细胞移植（allo-HSCT）后最常见的长期并发症。肺cGVHD患者尤其具有非常差的预后。NK细胞是allo-HSCT后第一个重建的淋巴细胞亚群；然而，重组NK细胞对cGVHD的影响尚不清楚.这里,我们发现同种异体受者表现出明显的肺cGVHD。令人惊讶的是,重建的NK细胞的缺失导致肺cGVHD的最大缓解。机械上,具有供体谱的重建NK细胞调节肺部炎症微环境以触发cGVHD。重构的NK细胞分泌IFN-γ和TNF-α诱导上皮细胞产生CXCL10，将巨噬细胞和CD4+T细胞募集到肺部。然后巨噬细胞和CD4+T细胞被炎症微环境激活，从而介导肺损伤。通过评估细胞能量的差异，我们发现具有高线粒体电位和促炎活性的CD74+NK细胞可触发肺cGVHD.此外，使用抗CD74抗体靶向消除CD74+NK细胞可显着减轻肺cGVHD，但保留CD74-NK细胞以发挥移植物抗白血病（GVL）作用。来自人类样本的数据证实了我们在小鼠模型中的发现。总的来说，我们的结果显示,重建的CD74+NK细胞可触发肺cGVHD,并提示给予CD74抗体是cGVHD患者的潜在治疗方法.
