Human Mesenchymal Stem Cells Induce T Cell Anergy and Downregulate T Cell Allo-Responses via the TH2 Pathway: Relevance to Tissue Engineering Human Heart Valves

Abstract

To generate an ''off the shelf'' tissue-engineered heart valve, the cells would need to be of allogeneic origin. Here, we report the possibility of using human bone marrow-derived mesenchymal stem cells (MSCs) as a suitable allogeneic cell source for tissue-engineered heart valves. Proliferative responses of primary and primed CD4+ T cells to allogeneic MSCs were examined. A protein microarray system was used to detect soluble factors from supernatants collected from the T cell assays. MSCs are poor stimulators of primary and primed CD4+ T cell proliferation, despite provision of B7-1 trans-co-stimulation. MSCs not only directly inhibited primary and primed T cell responses to allogeneic peripheral blood mononuclear cells (PBMCs), but 24-h pre-culture of T cells with MSCs suppressed subsequent T cell proliferative responses to allogeneic PBMCs in a contact-dependent manner. Analysis of supernatants revealed a distinctly different cytokine profile after co-culture of T cells with MSCs than with PBMCs or endothelial cells. Pro-inflammatory Th1 cytokines interleukin (IL)-1alpha and beta, interferon (IFN)gamma, and tumor necrosis factor (TNF)alpha were downregulated, whereas, anti-inflammatory Th2 cytokines IL-3, IL-5, IL-10, and IL-13 and the Th2 chemokine I-309, a chemoattractant for regulatory T cells, were upregulated. Further analysis revealed that after co-culture with MSCs, the T cells exhibited a regulatory phenotype (CD4+ CD25(lo) CD69(lo) FoxP3+). MSCs downregulate T cell responses through direct contact and secretion of anti-inflammatory and tolerogenic cytokines, which may involve the recruitment of regulatory T cells. This implies that allogeneic MSCs could be a suitable cell source for tissue engineering a heart valve.

Soluble Factors–Mediated Immunomodulatory Effects of Canine Adipose Tissue–Derived Mesenchymal Stem Cells

“…As shown in Fig. 6B and C, PGE2 MSCs, although other reports showed that IFN-γ production decreased when T cells were cocultured with MSCs [16,17]. Moreover, NK cells were shown to produce IFN-γ when they interacted with allogeneic and autologus hBM-MSCs [20].…”

“…MSCs can cause allogeneic immune cells to be suppressed through immunomodulatory factors that may be induced by interferon-γ (IFN-γ) secreted by activated T cells [30]. Moreover, it has been reported that MSCs can induce an increase in Th2 cells and regulatory T cells [16,17]; however, the exact mechanism of this immune modulation by MSCs is not well understood.…”

Mesenchymal stromal cells for treatment of arthritis

“…MSC downregulated T cell responses through direct contact and secretion of anti-inflammatory and tolerogenic cytokines, which may involve the recruitment of regulatory T cells [31]. The general effects are to skew the immune response towards anti-inflammatory/tolerant phenotypes, including the shift from Th1 towards Th2, downregulation of IFN-g production from NK and reduction in the antibody productions of B cells [32].…”

Immunosuppressive Activity of Adipose Tissue-Derived Mesenchymal Stem Cells in a Rat Model of Hind Limb Allotransplantation

“…Among these cells, bone marrowederived mesenchymal stem cells (BM-MSCs) possess immune privilege and immunosuppressive capacities [3] and can inhibit T-cell proliferation to allogeneic cellular and nonspecific mitogenic stimuli [4]. In addition, in vivo studies showed that infusion of allogeneic BM-MSCs have immunosuppressive activity [5] possibly through the preferential activation of CD4 þ CD25 þ Foxp3 þ regulatory T cells (T regs) [6].…”