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.