title: Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function.
abstract: Interferon-γ (IFN-γ)-preactivated mesenchymal stem cells (MSC-γ) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrow-derived MSC with interleukin-17A (MSC-17) to enhance T cell immunosuppression but not their immunogenicity. MSC-17, unlike MSC-γ, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When cocultured with phytohemagglutinin (PHA)-activated human T cells, MSCs-17 were potent suppressors of T cell proliferation. Furthermore, MSC-17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines, IFN-γ, tumor necrosis factor-α (TNF-α), and IL-2 when compared with untreated MSCs (UT-MSCs). T cell suppression by MSC-17 correlated with increased IL-6 but not with indoleamine 2,3-dioxygenase 1, cyclooxygenase 1, and transforming growth factor β-1. MSC-17 but not MSC-γ consistently induced CD4(+) CD25(high) CD127(low) FoxP3(+) regulatory T cells (iTregs) from PHA-activated CD4(+) CD25(-) T cells. MSC-induced iTregs expressed CD39, CD73, CD69, OX40, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), and glucocorticoid-induced TNFR-related protein (GITR). These suppressive MSCs-17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application.
authors.affiliation: School of Medicine, Faculty of Health Sciences, Adelaide, South Australia, Australia.|Centre for Stem Cell Research and Robinson Institute, School of Medical Sciences, Adelaide, South Australia, Australia.|Centre for Clinical and Experimental Transplantation, Adelaide, South Australia, Australia.
authors.forename: Kisha Nandini
authors.initials: KN
authors.lastname: Sivanathan
authors.affiliation: School of Medicine, Faculty of Health Sciences, Adelaide, South Australia, Australia.|Centre for Clinical and Experimental Transplantation, Adelaide, South Australia, Australia.
authors.forename: Darling M
authors.initials: DM
authors.lastname: Rojas-Canales
authors.affiliation: School of Medicine, Faculty of Health Sciences, Adelaide, South Australia, Australia.|Centre for Clinical and Experimental Transplantation, Adelaide, South Australia, Australia.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Hope
authors.affiliation: School of Medicine, Faculty of Health Sciences, Adelaide, South Australia, Australia.
authors.forename: Ravi
authors.initials: R
authors.lastname: Krishnan
authors.affiliation: Centre for Clinical and Experimental Transplantation, Adelaide, South Australia, Australia.|Central Northern Adelaide Renal Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Carroll
authors.affiliation: Centre for Stem Cell Research and Robinson Institute, School of Medical Sciences, Adelaide, South Australia, Australia.|Mesenchymal Stem Cell Group Laboratory, School of Medicine, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Stan
authors.initials: S
authors.lastname: Gronthos
authors.affiliation: Transplant Immunology Group, Garvin Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: Shane T
authors.initials: ST
authors.lastname: Grey
authors.affiliation: School of Medicine, Faculty of Health Sciences, Adelaide, South Australia, Australia.|Centre for Stem Cell Research and Robinson Institute, School of Medical Sciences, Adelaide, South Australia, Australia.|Centre for Clinical and Experimental Transplantation, Adelaide, South Australia, Australia.|Central Northern Adelaide Renal Transplantation Service, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Coates
mesh_terms: D002478:Cells, Cultured; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology* / Q000494:pharmacology*; D020381:Interleukin-17 / Q000276:immunology* / Q000494:pharmacology*; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: C508717:IL17A protein, human; D007155:Immunologic Factors; D020381:Interleukin-17
keywords: Immunomodulation; Interferon-gamma; Interleukin-17A; Mesenchymal stem cells; Regulatory T cells; T cells