Embryonic stem (ES) cells are regarded as a very promising source of differentiated cells for tissue regeneration. ES cell-derived cardiomyocytes could functionally replace irreversibly lost cardiac tissue in various animal models of ischaemic heart disease. However, clinical application of this therapeutic approach will be hampered by immunological rejection of transplanted cells by histoincompatible recipients. To address the question of immunological properties of murine ES cell-derived cardiomyocytes we have utilized a transgenic murine ES cell line D3αPIG engineered to express GFP and antibiotic resistance specifically in ES cell-derived heart cells. This cell line enabled us to highly purify GFP-positive cardiac progenitor cells and to specifically address the question of their immunogenic properties. To this end, we have determined their immunophenotype by flow cytometry, assessed their response to the inflammatory cytokine interferon gamma, assayed their physical interaction with cytotoxic T lymphocytes and tested their susceptibility to lysis by activated NK cells and cytotoxic T cells. These studies have demonstrated that ES cell-derived cardiomyocytes constitutively express very low levels of MHC class I molecules on their cell surface, which were strongly upregulated by interferon gamma. Interestingly, the cytotoxicity experiments revealed that ES cell-derived cardiac cells were resistant to killing by poly I:C activated syngeneic and allogeneic NK cells as well as by allogeneic cytotoxic T cells. Even strong upregulation of MHC class I molecules on the surface of cardiac cells by interferon gamma did not render them sensitive to lysis by immune effector cells, indicating that transplanted ES cell-derived cardiomyocytes might be less susceptible to rejection as compared to whole organ transplants. Ongoing studies are aimed at elucidating the molecular basis of this resistance and assessing the engraftment capacity and immunogenicity of ES cell-derived cardiomyocytes in vivo upon allotransplantation.