title: Mesenchymal stromal cells inhibit CD25 expression via the mTOR pathway to potentiate T-cell suppression.
abstract: Mesenchymal stromal cells (MSCs) are known to suppress T-cell activation and proliferation. Several studies have reported that MSCs suppress CD25 expression in T cells. However, the molecular mechanism underlying MSC-mediated suppression of CD25 expression has not been fully examined. Here, we investigated the mTOR pathway, which is involved in CD25 expression in T cells. We showed that MSCs inhibited CD25 expression, which was restored in the presence of an inducible nitric oxide synthase (iNOS) inhibitor. Since CD25 mRNA expression was not inhibited, we focused on determining whether MSCs modulated components of the mTOR pathway in T cells. MSCs increased the phosphorylation of liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK) and decreased the phosphorylation of ribosomal protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). In addition, the expression of 4E-BP1 increased dramatically in the presence of MSCs. An m7GTP pull-down assay showed increased binding of 4E-BP1 to the 5' cap-binding eukaryotic translation initiation factor 4E (eIF4E) complex in the presence of MSCs, which resulted in inhibition of mRNA translation. Treatment with 4EGI-1, a synthetic inhibitor of mRNA translation, also reduced CD25 expression in T cells. Polysome analysis confirmed decreased CD25 mRNA in the polysome-rich fraction in the presence of MSCs. Taken together, our results showed that nitric oxide, produced by MSCs, inhibits CD25 translation through regulation of the LKB1-AMPK-mTOR pathway to suppress T cells.
authors.affiliation: Department of Molecular Biomedicine, Translational Research Center, Inha University Hospital, IRIMS, Inha University School of Medicine, Incheon 22332, Republic of Korea.
authors.forename: Hyun Seung
authors.initials: HS
authors.lastname: Yoo
authors.affiliation: Department of Molecular Biomedicine, Translational Research Center, Inha University Hospital, IRIMS, Inha University School of Medicine, Incheon 22332, Republic of Korea.
authors.forename: Kyuheon
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Molecular Biomedicine, Translational Research Center, Inha University Hospital, IRIMS, Inha University School of Medicine, Incheon 22332, Republic of Korea.
authors.forename: Kwangmin
authors.initials: K
authors.lastname: Na
authors.affiliation: Department of Molecular Biomedicine, Translational Research Center, Inha University Hospital, IRIMS, Inha University School of Medicine, Incheon 22332, Republic of Korea.
authors.forename: Yong Xu
authors.initials: YX
authors.lastname: Zhang
authors.affiliation: SCM Lifescience Co., Ltd., Incheon 22332, Republic of Korea.
authors.forename: Hyun-Ja
authors.initials: HJ
authors.lastname: Lim
authors.affiliation: Department of Molecular Biomedicine, Translational Research Center, Inha University Hospital, IRIMS, Inha University School of Medicine, Incheon 22332, Republic of Korea.|SCM Lifescience Co., Ltd., Incheon 22332, Republic of Korea.|SunCreate Co., Ltd., Yangju, Gyeonggi-do 11416, Republic of Korea.
authors.forename: TacGhee
authors.initials: T
authors.lastname: Yi
authors.affiliation: Department of Molecular Biomedicine, Translational Research Center, Inha University Hospital, IRIMS, Inha University School of Medicine, Incheon 22332, Republic of Korea.|SCM Lifescience Co., Ltd., Incheon 22332, Republic of Korea.
authors.forename: Sun U
authors.initials: SU
authors.lastname: Song
authors.affiliation: Department of Molecular Biomedicine, Translational Research Center, Inha University Hospital, IRIMS, Inha University School of Medicine, Incheon 22332, Republic of Korea.|Convergent Research Center for Metabolism and Immunoregulation, Inha University, Incheon 22212, Republic of Korea.
authors.forename: Myung-Shin
authors.initials: MS
authors.lastname: Jeon
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; C508018:Il2ra protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D012333:RNA, Messenger; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases