title: ICOSL expression in human bone marrow-derived mesenchymal stem cells promotes induction of regulatory T cells.
abstract: Mesenchymal stem cells (MSCs) can modulate lymphocyte proliferation and function. One of the immunomodulatory functions of MSCs involves CD4+CD25+FoxP3+regulatory T cells (Tregs), which negatively regulate inflammatory responses. MSC-mediated Treg induction is supposed to be regulated by mechanisms requiring both soluble and cell contact-dependent factors. Although the involvement of soluble factors has been revealed, the contact-dependent mechanisms in MSC-mediated Treg induction remain unclear. We attempted to identify molecule(s) other than secreted factors that are responsible for MSC-mediated Treg induction and to uncover the underlying mechanisms. Under in vitro Treg-inducing conditions, ICOSL expression in MSCs coincided with Treg induction in co-cultures of MSCs with CD4+T cells. When cultured in a transwell plate, MSCs failed to induce Tregs. Neutralization or knockdown of ICOSL significantly reduced Tregs and their IL-10 release. ICOSL overexpression in MSCs promoted induction of functional Tregs. ICOSL-ICOS signaling promoted Treg differentiation from CD4+T cells through activation of the phosphoinositide 3-kinase-Akt pathway. MSCs primed with Interleukin-1β significantly induced Tregs through ICOSL upregulation. We demonstrated that the Treg-inducing activity of MSCs is proportionate to their basal ICOSL expression. This study provides evidence that ICOSL expression in human MSCs plays an important role in contact-dependent regulation of MSC-mediated Treg induction.
authors.affiliation: Translational Research Center, Inha University School of Medicine, Incheon, Republic of Korea.|Drug Development Program, Department of Biomedical Sciences, Inha University School of Medicine, Incheon, Republic of Korea.
authors.forename: Hyun-Joo
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Translational Research Center, Inha University School of Medicine, Incheon, Republic of Korea.|Drug Development Program, Department of Biomedical Sciences, Inha University School of Medicine, Incheon, Republic of Korea.|SCM Lifesciences Co. Ltd., Incheon, Republic of Korea.
authors.forename: Si-Na
authors.initials: SN
authors.lastname: Kim
authors.affiliation: Translational Research Center, Inha University School of Medicine, Incheon, Republic of Korea.
authors.forename: Myung-Shin
authors.initials: MS
authors.lastname: Jeon
authors.affiliation: Translational Research Center, Inha University School of Medicine, Incheon, Republic of Korea.|SunCreate Co. Ltd., Yangju, Republic of Korea.
authors.forename: TacGhee
authors.initials: T
authors.lastname: Yi
authors.affiliation: Translational Research Center, Inha University School of Medicine, Incheon, Republic of Korea.|SCM Lifesciences Co. Ltd., Incheon, Republic of Korea.
authors.forename: Sun U
authors.initials: SU
authors.lastname: Song
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation / Q000235:genetics; D018920:Coculture Techniques; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000235:genetics*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics*; D016753:Interleukin-10 / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics*; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: C556692:ICOS protein, human; C498514:ICOSLG protein, human; C508609:IL10 protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D016753:Interleukin-10; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt