S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission  

作　　者：Linlu Tian Yongxia Wu Hee-Jin Choi Xiaohui Sui Xinlei Li M.Hanief Sofi Mohamed Faisal Kassir Xiao Chen Shikhar Mehrotra Besim Ogretmen Xue-zhong Yu 

机构地区：[1]Department of Microbiology&Immunology,Medical University of South Carolina,Charleston,SC,USA [2]Department of Microbiology&Immunology,Medical College of Wisconsin,Milwaukee,WI,USA [3]Department of Medicine,Medical College of Wisconsin,Milwaukee,WI,USA [4]Department of Biochemistry&Molecular Biology,Medical University of South Carolina,Charleston,SC,USA [5]Department of Surgery,Medical University of South Carolina,Charleston,SC,USA [6]Hollings Cancer Center,Medical University of South Carolina,Charleston,SC,USA [7]The Cancer Center,Medical College of Wisconsin,Milwaukee,WI,USA

出　　处：《Cellular & Molecular Immunology》2022年第11期1235-1250,共16页中国免疫学杂志（英文版）

基　　金：This work is supported in part by SmartState Cancer Stem Cell Biology&Therapy Program and by R01 grants from the National Institutes of Health,including AI118305,HL140953 and CA258440(X.-Z.Y.).

摘　　要：Graft-versus-host disease (GVHD) significantly contributes to patient morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HSCT). Sphingosine-1-phosphate (S1P) signaling is involved in the biogenetic processes of different immune cells. In the current study, we demonstrated that recipient sphingosine kinase 1 (Sphk1), but not Sphk2, was required for optimal S1PR1-dependent donor T-cell allogeneic responses by secreting S1P. Using genetic and pharmacologic approaches, we demonstrated that inhibition of Sphk1 or S1PR1 substantially attenuated acute GVHD (aGVHD) while retaining the graft-versus-leukemia (GVL) effect. At the cellular level, the Sphk1/S1P/S1PR1 pathway differentially modulated the alloreactivity of CD4+ and CD8+ T cells;it facilitated T-cell differentiation into Th1/Th17 cells but not Tregs and promoted CD4+ T-cell infiltration into GVHD target organs but was dispensable for the CTL activity of allogeneic CD8+ T cells. At the molecular level, the Sphk1/S1P/S1PR1 pathway augmented mitochondrial fission and increased mitochondrial mass in allogeneic CD4+ but not CD8+ T cells by activating the AMPK/AKT/mTOR/Drp1 pathway, providing a mechanistic basis for GVL maintenance when S1P signaling was inhibited. For translational purposes, we detected the regulatory efficacy of pharmacologic inhibitors of Sphk1 and S1PR1 in GVHD induced by human T cells in a xenograft model. Our study provides novel mechanistic insight into how the Sphk1/S1P/S1PR1 pathway modulates T-cell alloreactivity and validates Sphk1 or S1PR1 as a therapeutic target for the prevention of GVHD and leukemia relapse. This novel strategy may be readily translated into the clinic to benefit patients with hematologic malignancies and disorders.

关 键 词：Sphk1 S1P S1PR GVHD GVL mitochondrial fission 

分 类 号：R392[医药卫生—免疫学]