期刊
STEM CELLS
卷 33, 期 9, 页码 2850-2863出版社
WILEY
DOI: 10.1002/stem.2075
关键词
Mesenchymal stem cells; Interleukin-17A; Interferon-gamma; Regulatory T cells; T cells; Immunomodulation
资金
- Hospital Research Foundation, The Queen Elizabeth Hospital, Adelaide, South Australia
- University of Adelaide
- Transplantation Society
- Walter and Dorothy Trust Fund, University of Adelaide
- Transplantation Society of Australia and New Zealand
Interferon-gamma (IFN-gamma)-preactivated mesenchymal stem cells (MSC-gamma) 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-gamma, 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-gamma, tumor necrosis factor-alpha (TNF-alpha), 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 beta-1. MSC-17 but not MSC-gamma 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.
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