Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function

Kisha Nandini Sivanathan, Darling M. Rojas-Canales, Christopher M. Hope, Ravi Krishnan, Robert P. Carroll, Stan Gronthos, Shane T. Grey, Patrick T. Coates

Research output: Contribution to journalArticle

50 Citations (Scopus)

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+CD25highCD127lowFoxP3+ 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.

Original languageEnglish
Pages (from-to)2850-2863
Number of pages14
JournalStem Cells
Volume33
Issue number9
DOIs
Publication statusPublished - 1 Sep 2015

Keywords

  • Immunomodulation
  • Interferon-gamma
  • Interleukin-17A
  • Mesenchymal stem cells
  • Regulatory T cells
  • T cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Sivanathan, K. N., Rojas-Canales, D. M., Hope, C. M., Krishnan, R., Carroll, R. P., Gronthos, S., ... Coates, P. T. (2015). Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function. Stem Cells, 33(9), 2850-2863. https://doi.org/10.1002/stem.2075