The Negative Co-Signaling Molecule B7-H4 Is Expressed by Human Bone Marrow–Derived Mesenchymal Stem Cells and Mediates its T-Cell Modulatory Activity

Abstract

Though experimental evidence shows that human bone marrow-derived mesenchymal stem cells (hBMSCs) are able to suppress T-cell activation and proliferation, the precise mechanisms are still not completely understood. Here, we investigated the role of the negative costimulatory molecule B7-H4 in the immunosuppressive effect of hBMSCs on T-cell activation. We showed that B7-H4 expresses abundantly on hBMSCs assessed by reverse transcription, immunofluorescence staining, and flow cytometric analysis. Further studies demonstrated that B7-H4 expressed on hBMSCs inhibits T-cell activation and proliferation via induction of cell cycle arrest and inhibition of NF-kappaB nuclear translocation. Blocking B7-H4 would decrease the secretion of transforming growth factor-beta1 (TGF-beta1) in the supernatant of activated T cells co-cultured with hBMSCs. Addition of neutralizing antibodies against B7-H4 significantly attenuated the inhibitory effects of hBMSCs on T-cells. Thus, our study established the novel role of B7-H4 molecule in the suppressive effect of hBMSCs on T-cell activation and proliferation. Taken together, these results highlight the complex role of hBMSCs in regulating the immune response, asserting the possibility of their therapeutic application in transplantation, the treatment of graft-versus-host disease (GVHD), and autoimmune diseases.

Regulation of Mouse Microglia Activation and Effector Functions by Bone Marrow-Derived Mesenchymal Stem Cells

“…Important mediators secreted by MSCs are prostaglandin E2 (PGE2) [13,14], indolamine 2,3-dioxygenase enzyme [15,16], nitric oxide [17,18], transforming growth factor-beta, and hepatocyte growth factor [8,19]. In addition, MSCs have been shown to express the coinhibitory molecules B7-H1 and B7-H4 [20,21], the notch ligand Jagged-1 [22], and galectin-1 [23] on their surface, which negatively interfere with immune responses. Furthermore, maximum anti-inflammatory and immunosuppressive effects can be evoked if MSCs are activated in a proinflammatory microenvironment by the presence of cytokines such as interferon-gamma, tumor necrosis factor-alpha (TNF-a), and/or interleukin-1-beta (IL-1b) [24,25].…”

Novel Immunomodulatory Markers Expressed by Human WJ-MSC: an Updated Review in Regenerative and Reparative Medicine

“…In vitro data from our group recently demonstrated that WJ-MSC do express relevant immunomodulatory molecules both in their naïve and differentiated state, as demonstrated for osteogenic, adipogenic and hepatogenic differentiation protocols [56,57].…”

Mesenchymal Stem Cells: Immunology and Therapeutic Benefits

“…Both soluble mediators and modulation exerted via complex networks of cytokines and costimulatory molecules appear to play a role in MSC regulation of T cells, and these mechanisms invoke both contact-dependent and -independent pathways. Although many of the studies use MSC-conditioned medium, both contact-dependent andindependent mechanisms are probably invoked in the therapeutic use of MSCs (20,71). In addition to cytokines, the network of costimulatory molecules is hypothesized to play a prominent role in modulating tolerance and inflammation.…”

“…The B7 family members-inducible co-stimulator (ICOS) ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1)-are expressed on professional APC cells, while B7-H4 and B7-H1 are expressed on hMSCs and on cells within non-lymphoid organs. These observations may provide a new means for regulating T-cell activation and tolerance in peripheral tissues (31,71,78). ICOS and PD-1 are expressed upon T-cell-induction, and they regulate previously activated T-cells (79).…”