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Type: Journal article
Title: Ephb and Ephrin-B interactions mediate human mesenchymal stem cell suppression of activated T-cells
Author: Nguyen, T.
Arthur, A.
Hayball, J.
Gronthos, S.
Citation: Stem Cells and Development, 2013; 22(20):2751-2764
Publisher: Mary Ann Liebert Inc Publ
Issue Date: 2013
ISSN: 1547-3287
Statement of
Thao M. Nguyen, Agnes Arthur, John D. Hayball, and Stan Gronthos
Abstract: Mesenchymal stromal/stem cells (MSC) express the contact-dependent erythropoietin-producing hepatocellular (Eph) receptor tyrosine kinase family and their cognate ephrin ligands, which are known to regulate thymocyte maturation and selection, T-cell transendothelial migration, activation, co-stimulation, and proliferation. However, the contribution of Eph/ephrin molecules in mediating human MSC suppression of activated T-cells remains to be determined. In the present study, we showed that EphB2 and ephrin-B2 are expressed by ex vivo expanded MSC, while the corresponding ligands, ephrin-B1 and EphB4, respectively, are highly expressed by T-cells. Initial studies demonstrated that EphB2-Fc and ephrin-B2-Fc molecules suppressed T-cell proliferation in allogeneic mixed lymphocyte reaction (MLR) assays compared with human IgG-treated controls. While the addition of a third-party MSC population demonstrated dramatic suppression of T-cell proliferation responses in the MLR, blocking the function of EphB2 or EphB4 receptors using inhibitor binding peptides significantly increased T-cell proliferation. Consistent with these observations, shRNA EphB2 or ephrin-B2 knockdown expression in MSC reduced their ability to inhibit T-cell proliferation. Importantly, the expression of immunosuppressive factors, indoleamine 2, 3-dioxygenase, transforming growth factor-β1, and inducible nitric oxide synthase expressed by MSC, was up-regulated after stimulation with EphB4 and ephrin-B1 in the presence of interferon (IFN)-γ, compared with untreated controls. Conversely, key factors involved in T-cell activation and proliferation, such as interleukin (IL)-2, IFN-γ, tumor necrosis factor-α, and IL-17, were down-regulated by T-cells treated with EphB2 or ephrin-B2 compared with untreated controls. Studies utilizing signaling inhibitors revealed that inhibition of T-cell proliferation is partly mediated through EphB2-induced ephrin-B1 reverse signaling or ephrin-B2-mediated EphB4 forward signaling by activating Src, PI3Kinase, Abl, and JNK kinase pathways, activated by tyrosine phosphorylation. Taken together, these observations suggest that EphB/ephrin-B interactions play an important role in mediating human MSC inhibition of activated T cells.
Keywords: T-Lymphocytes
Mesenchymal Stem Cells
Receptor, EphB2
Receptor, EphB4
RNA, Small Interfering
Lymphocyte Culture Test, Mixed
Coculture Techniques
Lymphocyte Activation
Signal Transduction
Cell Proliferation
Gene Expression Regulation
Indoleamine-Pyrrole 2,3,-Dioxygenase
Nitric Oxide Synthase Type II
Transforming Growth Factor beta1
Primary Cell Culture
Rights: © Mary Ann Liebert, Inc.
DOI: 10.1089/scd.2012.0676
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Appears in Collections:Aurora harvest
Medical Sciences publications

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