Neural progenitors derived from human embryonic stem cells are targeted by allogeneic T and natural killer cells

Abstract

Neural progenitor cells (NPC) of foetal origin or derived from human embryonic stem cells (HESC) have the potential to differentiate into mature neurons after transplantation into the central nervous system, opening the possibility of cell therapy for neurodegenerative disorders. In most cases, the transplanted NPC are genetically unrelated to the recipient, leading to potential rejection of the transplanted cells. Very few data provide reliable information as to the potential immune response of allogeneic neural progenitors derived from HESC. In this study, we analyzed in vitro the allogeneic immune response of T lymphocytes and natural killer (NK) cells to NPC derived from HESC or of foetal origin. We demonstrate that NPC induce T-cell stimulation and a strong NK cytotoxic response. NK-cell activity is unrelated to MHC-I expression but driven by the activating NKG2D receptor. Cyclosporine and dexamethasone previously used in clinical studies with foetal NPC did not only fail to prevent NK alloreactivity but strongly inhibited the terminal maturation from NPC into mature neurons. We conclude that allogenic transplantation of NPC in the central nervous system will most likely require an immunosuppressive regimen targeting allogenic T and NK cells, whereas possible interference with the differentiation of NPC needs to be carefully evaluated.

Human Parthenogenetic Embryonic Stem Cell-Derived Neural Stem Cells Express HLA-G and Show Unique Resistance to NK Cell-Mediated Killing

“…Similar to earlier reports on N hESCs and their differentiated progeny, we observed that PG NSCs expressed low levels of HLA-I proteins but no HLA-II or costimulatory molecules (16,18,19). HLA-I expression in PG NSCs was increased by IFN-γ treatment and reached PBMC levels as reported for N hESCs (16).…”

“…N NSCs induce proliferation of allogeneic T cells in a mixed lymphocyte reaction (MLR) despite the absence of costimulatory molecules (19,20). To address this property for PG NSCs, we recorded the response of healthy donor PMBCs to irradiated PG NSCs in allogeneic MLR reactions.…”

“…Whether or not N hESCs stimulate allogeneic T cell proliferation remains contradictory (17,18). However, N hESC-derived neural stem cells (N NSCs) stimulate the proliferation of peripheral blood mononuclear cells (PBMCs) in vitro, particularly of CD4 + T cells; N NSCs also are susceptible to natural killer (NK) cell-mediated lysis (19,20). In vivo analyses further showed that xeno-rejection of hESCs and of hESCderived cells is mainly T cell-mediated and that NK cells also are involved (21,22).…”

Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells

“…Besides the lack of MHC I on target cells, the activation of additional stimulatory NK receptors is necessary to trigger NK killing (Bryceson et al, 2006), and the expression of stimulating NK ligands can lead to lysis even in the presence of MHC I (Cerwenka et al, 2001). Murine ESCs have been shown to express high levels of the NKG2D ligands REA-1, H60, MULT-1 (Bonde and Zavazava, 2006;Dressel et al, 2008;Frenzel et al, 2009) and ICAM-1 (Frenzel et al, 2009), and blocking of these receptors prevents cell lysis (Frenzel et al, 2009;Preynat-Seauve et al, 2009). Murine ESC-derived cardiomyocytes, however, which are negative for MHC I but also negative for NKG2D ligands, were spared by NK cells (Frenzel et al, 2009).…”

Human Pluripotent Stem Cell Therapy for Huntington's Disease: Technical, Immunological, and Safety Challenges

“…Potential hESC-derived grafts would likely require no more immunosuppression than what is currently used for fetal neural grafts. It is worth mentioning, however, that 1 study [123] has shown that such a treatment may inhibit differentiation from PSC. This issue should be specifically considered before clinical implementation.…”