Michael Cuccione Childhood Cancer Research Program, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver.
Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran.
Haematologica. 2023 Mar 1;108(3):761-771. doi: 10.3324/haematol.2022.280653.
Chronic graft-versus-host disease (cGvHD) is a major cause of morbidity after hematopoietic stem cell transplantation (HSCT). In large patient populations, we have shown a CD56bright natural killer (NK) population to strongly associate with a lack of cGvHD and we hypothesize that these cells function to suppress cGvHD. We aimed to isolate and define the characteristics of regulatory NK (NKreg) cells associated with suppression of cGvHD. Immunophenotypic evaluation of a large pediatric population found the CD56bright NK population associated with a lack of cGvHD to be perforin-, Granzyme B-, and CD335+. Transcriptome analysis of a small patient cohort of CD56bright compared to CD56dim NK cells found the NKreg cells to also overexpress Granzyme K, IL-7R, GPR183, RANK, GM-CSFR, TCF7, and IL23A. Further analysis of this CD56bright NKreg population found a subpopulation that overexpressed IRF1, and TNF. We also found that viable NKreg cells may be isolated by sorting on CD56+ and CD16- NK cells, and this population can suppress allogeneic CD4+ T cells, but not Treg cells or CD8+ T cells through a non-cytolytic, cell-cell contact dependent mechanism. Suppression was not reliant upon the NKp44, NKp46, or GPR183 receptors. Additionally, NKreg cells do not kill leukemic cells. Moreover, this is the first paper to clearly establish that a CD56brightCD3-CD16-perforin- NKreg population associates with a lack of cGvHD and has several unique characteristics, including the suppression of helper T-cell function in vitro. With further investigation we may decipher the mechanism of NKreg suppression and operationalize expansion of NKreg cells associated with cGvHD suppression.
慢性移植物抗宿主病（cGvHD）是造血干细胞移植（HSCT）后发病的主要原因。在大型患者人群中，我们发现 CD56bright 自然杀伤（NK）细胞群与缺乏 cGvHD 强烈相关，我们假设这些细胞的功能是抑制 cGvHD。我们旨在分离和定义与抑制 cGvHD 相关的调节性 NK（NKreg）细胞的特征。对大量儿科患者人群的免疫表型评估发现，与缺乏 cGvHD 相关的 CD56bright NK 群体为穿孔素、颗粒酶 B 和 CD335+。对一小部分患者亚群的 CD56bright 与 CD56dim NK 细胞的转录组分析发现，NKreg 细胞也过度表达颗粒酶 K、IL-7R、GPR183、RANK、GM-CSFR、TCF7 和 IL23A。对该 CD56bright NKreg 群体的进一步分析发现，一个亚群过度表达 IRF1 和 TNF。我们还发现，通过对 CD56+和 CD16-NK 细胞进行分选，可以分离出有活力的 NKreg 细胞，该群体可以通过非细胞溶解、细胞间接触依赖的机制抑制同种异体 CD4+T 细胞，但不能抑制 Treg 细胞或 CD8+T 细胞。抑制作用不依赖于 NKp44、NKp46 或 GPR183 受体。此外，NKreg 细胞不会杀死白血病细胞。此外，这是第一篇明确建立 CD56brightCD3-CD16-穿孔素-NKreg 群体与缺乏 cGvHD 相关并具有几个独特特征的论文，包括体外抑制辅助 T 细胞功能。通过进一步研究，我们可能会破译 NKreg 抑制的机制，并实施与抑制 cGvHD 相关的 NKreg 细胞的扩增。
