Immunobiology of naïve and genetically modified HLA-class-I-knockdown human embryonic stem cells

Tobias Deuse, Martina Seifert, Neil Phillips, Andrew Fire, Dolly Tyan, Mark Kay, Philip S. Tsao, Xiaoqin Hua, Joachim Velden, Thomas Eiermann, Hans Dieter Volk, Hermann Reichenspurner, Robert C. Robbins, Sonja Schrepfer

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3029-3037
Number of pages9
JournalJournal of Cell Science
Volume124
Issue number17
DOIs
StatePublished - Sep 1 2011
Externally publishedYes

Keywords

  • HLA class I knockdown
  • Human embryonic stem cells
  • Immunology
  • Rejection

ASJC Scopus subject areas

  • Cell Biology

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