title: Role of natural-killer group 2 member D ligands and intercellular adhesion molecule 1 in natural killer cell-mediated lysis of murine embryonic stem cells and embryonic stem cell-derived cardiomyocytes.
abstract: The transplantation of cardiomyocytes derived from embryonic stem (ES) cells into infarcted heart has been shown to improve heart function in animal models. However, immune rejection of transplanted cells may hamper the clinical application of this approach. Natural killer (NK) cells could play an important role in this process in both autologous and allogeneic settings by eliminating cells expressing low levels of major histocompatibility complex (MHC) class I molecules. Here we characterize embryonic stem cell-derived cardiomyocytes (ESCM) in terms of their sensitivity to NK cells. We show that despite expression of very low levels of MHC class I molecules, murine ESCM were neither recognized nor lysed by activated syngeneic NK cells in vitro. In contrast, undifferentiated ES cells expressing similarly low levels of MHC class I molecules as ESCM were recognized and lysed by NK cells. This differential susceptibility results from the differential expression of ligands for the major activating natural killer cell receptor natural-killer group 2 member D (NKG2D) and intercellular adhesion molecule 1 (ICAM-1) on ES cells versus ESCM. NKG2D ligands and ICAM-1 were expressed on ES cells but were absent from ESCM. Undifferentiated ES cells were lysed by NK cells in a perforin-dependent manner. However, simultaneous blockade of NKG2D and ICAM-1 by antibodies inhibited this killing. These data suggest that in the course of differentiation ESCM acquire resistance to NK cell-mediated lysis by downregulating the expression of ligands required for activation of NK cell cytotoxicity.
authors.affiliation: Institute for Neurophysiology, University of Cologne, Cologne, Germany.
authors.forename: Lukas P
authors.initials: LP
authors.lastname: Frenzel
authors.forename: Zeinab
authors.initials: Z
authors.lastname: Abdullah
authors.forename: Anja K
authors.initials: AK
authors.lastname: Kriegeskorte
authors.forename: Rebecca
authors.initials: R
authors.lastname: Dieterich
authors.forename: Nadin
authors.initials: N
authors.lastname: Lange
authors.forename: Dirk H
authors.initials: DH
authors.lastname: Busch
authors.forename: Martin
authors.initials: M
authors.lastname: Krönke
authors.forename: Olaf
authors.initials: O
authors.lastname: Utermöhlen
authors.forename: Jürgen
authors.initials: J
authors.lastname: Hescheler
authors.forename: Tomo
authors.initials: T
authors.lastname: Sarić
mesh_terms: D000818:Animals; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015395:Histocompatibility Antigens Class I; D055655:NK Cell Lectin-Like Receptor Subfamily K; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma