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HLA-E-expressing pluripotent stem cells escape allogeneic responses and lysis by NK cells

  • Author(s): Gornalusse, GG
  • Hirata, RK
  • Funk, SE
  • Riolobos, L
  • Lopes, VS
  • Manske, G
  • Prunkard, D
  • Colunga, AG
  • Hanafi, L-A
  • Clegg, DO
  • Turtle, C
  • Russell, DW
  • et al.

Published Web Location

https://doi.org/10.1038/nbt.3860
Abstract

Polymorphisms in the human leukocyte antigen (HLA) class I genes can cause the rejection of pluripotent stem cell (PSC)-derived products in allogeneic recipients. Disruption of the Beta-2 Microglobulin (B2M) gene eliminates surface expression of all class I molecules, but leaves the cells vulnerable to lysis by natural killer (NK) cells. Here we show that this 'missing-self' response can be prevented by forced expression of minimally polymorphic HLA-E molecules. We use adeno-associated virus (AAV)-mediated gene editing to knock in HLA-E genes at the B2M locus in human PSCs in a manner that confers inducible, regulated, surface expression of HLA-E single-chain dimers (fused to B2M) or trimers (fused to B2M and a peptide antigen), without surface expression of HLA-A, B or C. These HLA-engineered PSCs and their differentiated derivatives are not recognized as allogeneic by CD8+ T cells, do not bind anti-HLA antibodies and are resistant to NK-mediated lysis. Our approach provides a potential source of universal donor cells for applications where the differentiated derivatives lack HLA class II expression.

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