Lymphocyte Cell-Cycle Inhibition by HLA-G Is Mediated by Phosphatase SHP-2 and Acts on the mTOR Pathway

Human leukocyte antigen G (HLA-G) is involved in regulating T-cell responses through its interaction with inhibitory receptors belonging to the immunoglobulin-like transcript family (ILT). In this context, we investigated the pathways involved in the control of cell-cycle entry of T cells following HLA-G interaction with its inhibitory receptor. We show that HLA-G acts through its interaction with the LILRB1 receptor expressed on T lymphocytes. Both HLA-G and LILRB1 antibodies block the inhibitory effect of HLA-G and restore T-cell proliferation. The interaction of HLA-G with T lymphocytes is associated with phosphorylation of SHP-2 phosphatase, but not SHP-1. In addition, in activated T cells, their incubation with HLA-G is not associated with a decrease in the TCR or CD28 downstream pathways, but is associated with dephosphorylation of the mTOR molecule and p70S6K. In contrast, Akt, which acts upstream of mTOR, is not affected by HLA-G. The inhibition of SHP-2 by NSC-87877(5 µM), a chemical inhibitor of SHP-2, or the use of siRNA, abrogates dephosphorylation of mTOR and impairs the overexpression of p27kip in the presence of HLA-G. Together, these results indicate that HLA-G is associated with activation of phosphatase SHP-2, which inhibits the mTOR pathway and favors the inhibition of the cell-cycle entry of human-activated T cells

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

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