Inflammatory Cytokine-Induced Intercellular Adhesion Molecule-1 and Vascular Cell Adhesion Molecule-1 in Mesenchymal Stem Cells Are Critical for Immunosuppression

Abstract

Cell–cell adhesion mediated by ICAM-1 and VCAM-1 is critical for T cell activation and leukocyte recruitment to the inflammation site and, therefore, plays an important role in evoking effective immune responses. However, we found that ICAM-1 and VCAM-1 were critical for mesenchymal stem cell (MSC)-mediated immunosuppression. When MSCs were cocultured with T cells in the presence of T cell Ag receptor activation, they significantly upregulated the adhesive capability of T cells due to the increased expression of ICAM-1 and VCAM-1. By comparing the immunosuppressive effect of MSCs toward various subtypes of T cells and the expression of these adhesion molecules, we found that the greater expression of ICAM-1 and VCAM-1 by MSCs, the greater the immunosuppressive capacity that they exhibited. Furthermore, ICAM-1 and VCAM-1 were found to be inducible by the concomitant presence of IFN-γ and inflammatory cytokines (TNF-α or IL-1). Finally, MSC-mediated immunosuppression was significantly reversed in vitro and in vivo when the adhesion molecules were genetically deleted or functionally blocked, which corroborated the importance of cell–cell contact in immunosuppression by MSCs. Taken together, these findings reveal a novel function of adhesion molecules in immunoregulation by MSCs and provide new insights for the clinical studies of antiadhesion therapies in various immune disorders.

The Regenerative Medicine Laboratory: Facilitating Stem Cell Therapy for Equine Disease

“…MSCs secrete soluble mediators and directly interact with T-cells to modulate their activity [29,36,37]. MSCs can induce apoptosis of activated T cells, induce cell cycle arrest, decrease T-cell proliferation [30,38] and alter T cell phenotype.…”

“…MSCs target T-cell subsets (CD4+, CD8+, CD2+ and CD3+ subpopulations) equally [30]. MSCs in direct contact with lymphocytes may inhibit lymphocyte apoptosis via the secretion of IL-6 or nitric oxide (NO) [35][36][37]. MSCs activated by IFN-γ, up-regulate adhesion molecules, including intracellular adhesion molecule-1 (CD54; ICAM-1) and vascular cell adhesion molecule-1 (CD106; VCAM-1) [37].…”

“…MSCs in direct contact with lymphocytes may inhibit lymphocyte apoptosis via the secretion of IL-6 or nitric oxide (NO) [35][36][37]. MSCs activated by IFN-γ, up-regulate adhesion molecules, including intracellular adhesion molecule-1 (CD54; ICAM-1) and vascular cell adhesion molecule-1 (CD106; VCAM-1) [37]. In many models, direct contact between MSCs and T cells facilitates MSC immunosuppressive capacity.…”

“…In many models, direct contact between MSCs and T cells facilitates MSC immunosuppressive capacity. This direct association is presumed to facilitate the actions of locally produced, short-acting mediators such as NO [37].…”

Immune Effects of Mesenchymal Stromal Cells in Experimental Stroke

“…This has been demonstrated in an in-vivo model of GvHD, where MSCs were only immunosuppressive after IFNginduced synthesis of nitric oxide (Ren et al, 2008). Inflammatory cytokines like IFNg, TNFa, and IL-1 induce the expression of adhesion molecules such as intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 on the surface of MSCs, which appears to be mandatory for the induction of cell contact-dependent immunosuppressive functions (Ren et al, 2010). However, our cytometric bead array data suggest that systemic TNFa-and IFNglevels are extremely low after MCAo, which may prevent immunosuppressive activities of the transplanted mMSCs.…”