Mutual Interaction between Human Multipotent Adult Progenitor Cells and NK Cells

Abstract

Human multipotent adult progenitor cells (hMAPCs) are isolated from bone marrow with a more extensive expansion capacity compared to human mesenchymal stem cells (hMSCs) and with the ability to differentiate into endothelium. Like hMSCs, hMAPCs inhibit T-cell proliferation induced by alloantigens. In this study, we tested the interaction between hMAPCs and natural killer (NK) cells. We assessed the susceptibility of hMAPCs to NK cell-mediated lysis and the immunomodulation of hMAPCs on NK cell function during IL-2-driven stimulation and the cytolytic effector phase. Human MAPCs express the ligands PVR and ULBP-2/5/6, which are recognized by activating NK cell receptors. However, they also express MHC class I molecules, which induce inhibitory signals in NK cells. Freshly isolated NK cells at different effector:target ratios did not kill hMAPCs as assessed by an MTT and 51 Cr-release assay, while hMAPCs impaired the cytotoxic activity of resting NK cells against the NK-sensitive K562 leukemia cell line. By contrast, IL-2-stimulated NK cells were capable of killing hMAPCs, and preactivated NK cells were not influenced during their cytotoxic effector function against K562 cells by hMAPCs. When added during the 6-day preactivation phase with IL-2, hMAPCs dosedependently reduced NK cell proliferation in an IDO-dependent manner, but they did not influence the induction of cytotoxic capacity by IL-2. This study indicates that human MAPCs mutually interact with NK cells.

Multipotent adult progenitor cells improve the hematopoietic function in myelodysplasia

“…Like MSCs, MAPC cells have potent immunomodulatory effects in T cells [12][13][14], are nonimmunogenic for T-cell proliferation and cytokine production and even suppress T-cell activation and proliferation induced by alloantigens and mitogens in vitro. Human MAPC cells also have inhibitory effects in natural killer cells [15].…”

Clinical-Grade Human Multipotent Adult Progenitor Cells Block CD8+ Cytotoxic T Lymphocytes

“…Moreover, the T‐cell antigen‐specific cytotoxic activity (13.50% ± 3.71%) against EBV + B cells was significantly higher than the specific lysis of MultiStem. In some experiments ( n = 4), MultiStem cells were pretreated with interferon‐γ (IFN‐γ) (100 U/ml; Roche Diagnostics, Vilvoorde, Belgium, http://www.roche.com) for 48 hours to increase MHC class I molecule expression [28, 29]. However, this upregulation did not result in a higher sensitivity to CTL‐mediated lysis, confirming the immune‐privileged status of these clinical‐grade hMAPCs (data not shown).…”

“…Given the fact that MAPCs are among the noteworthy mesenchymal cell populations for clinical usage and have the advantage over MSCs of having large‐scale manufacturing and banking potential and therefore prompt availability, it is important to understand how these clinical‐grade MAPCs (MultiStem) interact with immune cells to validate their widespread therapeutic applicability. We found that hMAPCs are nonimmunogenic for alloreactive T‐cell proliferation; they impair allogeneic proliferative T‐cell responses, and they mutually interact with allogeneic NK cells in vitro [28, 29]. In this study, the influence of MultiStem cells on the cytotoxic function of CD8 + T cells was assessed by evaluating the immunogenicity of MultiStem and the susceptibility of the stem cell population toward CTL‐mediated lysis and by analyzing the MultiStem‐mediated modulation of CTL functionality.…”

Immunoregulatory effects of multipotent adult progenitor cells in a porcine ex vivo lung perfusion model

“…This immunoregulation is mainly described as the suppression of regulatory T cells in vitro [16] while the interaction with neutrophils, the most important effector cell in IRI, is largely unexplored. MSC and MAPC share similar immunoregulatory capabilities, although MAPC cells are found to be more potent compared to MSC in rhesus monkeys [32], human MSC and MAPC share similar immunoregulatory capabilities [23, 26, 33]. However, MAPC cell therapy is privileged over MSC for clinical translation since their low senescence and high population doubling allows for banking of large batches of cells from a single donor [15].…”

“…Therefore, we chose this cell type as bone marrow-derived cellular treatment for attenuation of ischemia-reperfusion injury in lung transplantation. Also, xenotransplantation and allotransplantation of these cells is thought to be safe due to a low expression of MHC I and lack of MHC II expression [14, 33]. These immune-privileged properties avoid recognition by the recipient’s immune system, and therefore, this immune mismatch is generally believed not to be an increased risk for patients.…”