RESUMO
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.
Assuntos
Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/metabolismo , Molécula 1 de Adesão Intercelular/fisiologia , Células Matadoras Naturais/fisiologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/fisiologia , Animais , Linhagem Celular , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe I/metabolismo , Imuno-Histoquímica , Molécula 1 de Adesão Intercelular/metabolismo , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
The activating receptor NKG2D recognizes a wide range of different ligands, some of which are primarily expressed in "stressed" tissues or on tumor cells. Until now, similar stimulatory effects on natural killer and CD8+ T cells have been described for all NKG2D ligands, and the NKG2D receptor/ligand system has therefore been interpreted as a sensor system involved in tumor immune surveillance and activation of immune responses. We show here that the NKG2D ligands H60 and MIC class 1 chain-related protein A (MICA) can also mediate strong suppressive effects on T cell proliferation. Responsiveness to H60- and MICA-mediated suppression requires IL-10 and involves a receptor other than NKG2D. These findings might provide explanations for the observation that strong in vivo NKG2D ligand expression, such as that on tumor cells, sometimes fails to support effective immune responses and links this observation to a distinct subgroup of NKG2D ligands.