T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression

Abstract

Human mesenchymal stem cells (MSCs) were evaluated for their ability to activate allogeneic T cells in cell mixing experiments. Phenotypic characterization of MSCs by flow cytometry showed expression of MHC Class I alloantigens, but minimal expression of Class II alloantigens and costimulatory molecules, including CD80 (B7-1), CD86 (B7-2), and CD40. T cells purified from peripheral blood mononuclear cells (PBMCs) did not proliferate to allogeneic MSCs. Lack of response was not due to a deficiency of costimulation, since retroviral transduction of MSCs with either B7-1 or B7-2 costimulatory molecules did not result in lymphoproliferation. Although these results suggested that MSCs were immunologically inert or potentially tolerogenic, T cells cultured with MSCs produced IFN-gamma and displayed secondary kinetics to restimulation with PBMCs, indicating alloantigen priming rather than tolerance induction by the MSCs. To determine whether MSCs suppressed alloreactive T cells, MSCs were added to primary mixed lymphocyte reaction (MLR) cultures. MSCs suppressed cell proliferation when added at the initiation of culture or when added to an ongoing MLR culture. Suppression was dose-dependent, genetically unrestricted, and occurred whether or not MSCs were pretreated with IFN-gamma. MSCs in transwell chambers suppressed primary MLR cultures, indicating that suppression was mediated by soluble molecules. Analysis of cytokines in suppressed MLR cultures demonstrated up-regulation of IFN-gamma and IL-10, and down-regulation of TNF-alpha production relative to control cultures. We conclude that MSCs can initiate activation of alloreactive T cells, but do not elicit T cell proliferative responses due to active suppressive mechanisms.

Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells

“…Indeed, this discrepancy between in vitro and in vivo MSC suppression studies is reminiscent of the conundrum regarding the mechanisms of suppression of murine Tregs, which also display distinct behaviours in vitro and in vivo [23]. Our results also highlight important differences between mouse and human MSCs [24,25]. Glennie et al [25] reported that human MSC-mediated inhibition induces an unresponsive T cell profile that can be reverted by the addition of exogenous IL-2.…”

How stem cells speak with host immune cells in inflammatory brain diseases

“…In vitro, both MSCs and NPCs are MHC-I low/medium and MHC-II negative (Klyushnenkova et al, 2005;Le Blanc et al, 2003;Pluchino et al, 2005Pluchino et al, , 2009a, but upregulation of MHC-I and -II expression is observed after long-term neurosphere expansion (Laguna Goya et al, 2011;Odeberg et al, 2005) or NPC exposure to proinflammatory cytokines such as interferon (IFN)-γ or tumor necrosis factor (TNF)-α (Johansson et al, 2008). Under basal growth conditions the co-stimulatory molecules CD80/ B7.1, CD86/B7.2 and CD40 are also absent in both MSCs and NPCs (Odeberg et al, 2005;Tse et al, 2003).…”

Immunoregulatory function of mesenchymal stem cells

“…The MSC capacity of inducing proliferative responses by allogeneic PBMC represents a controversial issue [14,25,26,28]; notably, however, both human and murine MSC are generally considered to be poorly immunogenic cells. MSC can also produce a variety of growth factors, cytokines, chemokines and proteases that are likely to play a role either in their immunomodulatory or in their migratory function [29][30][31].…”