RT Journal Article SR Electronic T1 Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells JF Journal of Cell Science JO J. Cell Sci. FD The Company of Biologists Ltd SP 3029 OP 3037 DO 10.1242/jcs.087718 VO 124 IS 17 A1 Deuse, Tobias A1 Seifert, Martina A1 Phillips, Neil A1 Fire, Andrew A1 Tyan, Dolly A1 Kay, Mark A1 Tsao, Philip S. A1 Hua, Xiaoqin A1 Velden, Joachim A1 Eiermann, Thomas A1 Volk, Hans-Dieter A1 Reichenspurner, Hermann A1 Robbins, Robert C. A1 Schrepfer, Sonja YR 2011 UL http://jcs.biologists.org/content/124/17/3029.abstract AB Human embryonic stem cells (hESCs) can serve as a universal cell source for emerging cell or tissue replacement strategies, but immune rejection of hESC derivatives remains an unsolved problem. Here, we sought to describe the mechanisms of rejection for naïve hESCs and upon HLA class I (HLA I) knockdown (hESCKD). hESCs were HLA I-positive but negative for HLA II and co-stimulatory molecules. Transplantation of naïve hESC into immunocompetent Balb/c mice induced substantial T helper cell 1 and 2 (Th1 and Th2) responses with rapid cell death, but hESCs survived in immunodeficient SCID-beige recipients. Histology revealed mainly macrophages and T cells, but only scattered natural killer (NK) cells. A surge of hESC-specific antibodies against hESC class I, but not class II antigens, was observed. Using HLA I RNA interference and intrabody technology, HLA I surface expression of hESCKD was 88%–99% reduced. T cell activation after hESCKD transplantation into Balb/c was significantly diminished, antibody production was substantially alleviated, the levels of graft-infiltrating immune cells were reduced and the survival of hESCKD was prolonged. Because of their very low expression of stimulatory NK ligands, NK-susceptibility of naïve hESCs and hESCKD was negligible. Thus, HLA I recognition by T cells seems to be the primary mechanism of hESC recognition, and T cells, macrophages and hESC-specific antibodies participate in hESC killing.