Loss of Lkb1 impairs Treg function and stability to aggravate graft-versus-host disease after bone marrow transplantation  

作　　者：Xiuhua Su Qianqian Wang Wei Guo Xiaolei Pei Qing Niu Maolan Liu Yuanyuan Liu Song Chen Sizhou Feng Yi He Donglin Yang Rongli Zhang Qiaoling Ma Weihua Zhai Aiming Pang Jialin Wei Yong Huang Yuechen Luo Mingzhe Han Xiaoming Feng Erlie Jiang 

机构地区：[1]State Key Laboratory of Experimental Hematology,National Clinical Research Center for Blood Diseases,Institute of Hematology&Blood Diseases Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,300020 Tianjin,China [2]Department of Hematology,the First Affiliated Hospital of Kunming Medical University,Hematology Research Center of Yunnan Province,650000 Kunming,China

出　　处：《Cellular & Molecular Immunology》2020年第5期483-495,共13页中国免疫学杂志（英文版）

基　　金：by grants from the National Basic Research Program of China(2015CB964402);the National Natural Science Foundation of China(81670171,81601369);the CAMS Innovation Fund for Medical Sciences(CIFMS,2016-I2M-1-003 and 2018-I2M-HL-013);the Tianjin Science Funds for Distinguished Young Scholars(17JCJQJC45800);the Nonprofit Central Research Institute Fund of the Chinese Academy of Medical Sciences(2018PT32034 and 2019-RC-HL-013).

摘　　要：Accumulating evidence suggests that a reduction in the number of Foxp3^(+) regulatory T cells(Tregs)contributes to the pathogenesis of acute graft-versus-host disease(aGVHD),which is a major adverse complication that can occur after allogeneic hematopoietic stem cell transplantation(allo-HSCT).However,the precise features and mechanism underlying the defects in Tregs remain largely unknown.In this study,we demonstrated that Tregs were more dramatically decreased in bone marrow compared with those in peripheral blood from aGVHD patients and that bone marrow Treg defects were negatively associated with hematopoietic reconstitution.Tregs from aGVHD patients exhibited multiple defects,including the instability of Foxp3 expression,especially in response to IL-12,impaired suppressor function,decreased migratory capacity,and increased apoptosis.Transcriptional profiling revealed the downregulation of Lkb1,a previously identified critical regulator of murine Treg identity and metabolism,and murine Lkb1-regulated genes in Tregs from aGVHD patients.Foxp3 expression in human Tregs could be decreased and increased by the knockdown and overexpression of the Lkb1 gene,respectively.Furthermore,a loss-of-function assay in an aGVHD murine model confirmed that Lkb1 deficiency could impair Tregs and aggravate disease severity.These findings reveal that Lkb1 downregulation contributes to multiple defects in Tregs in human aGVHD and highlight the Lkb1-related pathways that could serve as therapeutic targets that may potentially be manipulated to mitigate aGVHD.

关 键 词：allogeneic hematopoietic stem cell transplantation(allo-HSCT) acute graft-versus-host disease(aGVHD) LKB1 TREG 

分 类 号：R392[医药卫生—免疫学]