Long-Lasting Inhibitory Effects of Fetal Liver Mesenchymal Stem Cells on T-Lymphocyte Proliferation

Abstract

Human bone marrow mesenchymal stem cells (BM-MSC) are multipotent progenitor cells that have transient immunomodulatory properties on Natural Killer (NK) cells, Dendritic Cells (DC), and T cells. This study compared the use of MSC isolated from bone marrow and fetal liver (FL-MSC) to determine which displayed the most efficient immunosuppressive effects on T cell activation. Although both types of MSC exhibit similar phenotype profile, FL-MSC displays a much more extended in vitro life-span and immunomodulatory properties. When co-cultured with CD3/CD28-stimulated T cells, both BM-MSC and FL-MSC affected T cell proliferation by inhibiting their entry into the cell cycle, by inducing the down-regulation of phospho-retinoblastoma (pRb), cyclins A and D1, as well as up-regulating p27kip1expression. The T cell inhibition by MSC was not due to the soluble HLA-G5 isoform, but to the surface expression of HLA-G1, as shown by the need of cell-cell contact and by the use of neutralizing anti-HLA-G antibodies. To note, in a HLA-G-mediated fashion, MSC facilitated the expansion of a CD4low/CD8low T subset that had decreased secretion of IFN-γ, and an induced secretion of the immunomodulatory cytokine IL-10. Because of their longer lasting in vitro immunosuppressive properties, mainly mediated by HLA-G, and their more efficient induction of IL-10 production and T cell apoptosis, fetal liver MSC could be considered a new tool for MSC therapy to prevent allograft rejection.

Human Mesenchymal Stromal Cells from Adult and Neonatal Sources: A Comparative In Vitro Analysis of Their Immunosuppressive Properties Against T Cells

“…We noted that BM-MSCs, UCB-MSCs, and to a lesser extent PL-MSCs, suppressed the proliferation of anti-CD3/CD28-activated CD3 + T cells only in the presence of direct contact between the two cell populations; similar results were previously obtained with mouse BMMSCs [23]. Moreover, several studies have reported that a lack of cellular contact affects MSCs-mediated immunosuppression because the reduction of activated T-cell proliferation was less apparent [8,[20][21][22]30,46,47].…”

“…In this regard it has been shown that expression of adhesion molecules ICAM-I and VCAM-I on MSCs decline proliferation of splenocytes activated with anti-CD3 antibodies [48] and further, both adhesion molecules have the capacity to induce CTLA-4 expression on T cells [49], which is involved in inhibition of T-cell proliferation [33,34]. In addition, cell contact between MSCs and T cells increase expression of IL-10, HLA-G1, and HLA-G5 immunosuppression molecules [7,8,19,21], which are involved in the inhibition of T-cell proliferation. It appears that HLA-G1, whose expression is increased on MSCs cocultured with activated T cells [21], is the molecule responsible to stimulate initial secretion of IL-10, which stimulate HLA-G5 secretion in MSCs and through a positive feedback mechanism stimulate secretion of IL-10.…”

“…Programmed death ligand 1 (PD-L1) and human leukocyte antigen-G1 (HLA-G1) expression have been linked to the cell contact-dependent mechanisms [8,[19][20][21], while transforming growth factor beta (TGF-b), hepatocyte growth factor, interleukin-10 (IL-10), indoleamine 2,3-dioxygenase (IDO), nitric oxide, prostaglandin E2 (PGE 2 ), and human leukocyte antigen-G5 (HLA-G5) have been identified as secreted factors [1,5,8]. Currently, there is controversy regarding the need for direct contact between MSCs and T cells to inhibit T-cell proliferation [4,8,11,[19][20][21][22][23]. Additionally, studies of activation marker expression are also controversial.…”

Cord-Blood-Derived Mesenchymal Stromal Cells Downmodulate CD4+T-Cell Activation by Inducing IL-10-Producing Th1 Cells

“…It is noteworthy that despite previously published data suggesting the importance of IL-10 in MSC-mediated immunosuppression [40][41][42], to our knowledge, no one has yet demonstrated that the putative effects of IL-10 could be reversed by blocking the IL-10 pathway. Such a discrepancy may not only be explained by the redundancy of MSC-induced inhibitory mechanisms [43][44][45], but also by the simple fact that while IL-10 + IFNg + T-cells are being generated during the first stimulation by the presence of MSCs, their accumulation occurs too late to have any effect.…”

Identification of a novel HLA-G+ regulatory population in blood: expansion after allogeneic transplantation and de novo HLA-G expression at graft-versus-host disease sites

“…33 An association between HLA-G and T-cell tolerance was suggested by Naji et al 33 who found a correlation between soluble HLA-G plasma levels, percentages of CD3 + CD4 low and CD3 + CD8 low suppressor T cells, and graft acceptance in liver/kidney transplanted patients. In addition, in a very recent study, Giuliani et al 34 reported an in vitro expansion of CD3 + CD4 low and CD3 + CD8 low T cells by mesenchymal stem cells in an HLA-G mediated fashion.…”