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Type: Journal article
Title: Interleukin-17A induced human mesenchymal stem cells are superior modulators of immunological function
Author: Sivanathan, K.
Rojas-Canales, D.
Hope, C.
Krishnan, R.
Carroll, R.
Gronthos, S.
Grey, S.
Coates, P.
Citation: Stem Cells, 2015; 33(9):2850-2863
Publisher: AlphaMed Press
Issue Date: 2015
ISSN: 1549-4918
Statement of
Kisha Nandini Sivanathan, Darling Rojas-Canales, Christopher M. Hope, Ravi Krishnan, Robert P. Carroll, Stan Gronthos, Shane T. Grey, and Patrick T. Coates.
Abstract: Interferon-gamma 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 co-stimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When co-cultured with phytohemagglutinin (PHA) activated human T cells, MSC-17 were potent suppressors of T cell proliferation. Further, MSC-17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and IL-2 when compared to untreated MSC (UT-MSC). T cell suppression by MSC-17 correlated with increased IL-6 but not indoleamine 2,3-dioxygenase 1 (IDO1), cyclooxygenase 1 (Cox-1), transforming growth factor beta-1 (TGF-β1). 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 MSC-17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application.
Keywords: Mesenchymal Stem Cells; Interleukin - 17A; Interferon - gamma; regulatory T cells; T cells; immunomodulation
Rights: © 2015 AlphaMed Press
DOI: 10.1002/stem.2075
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