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Cited by 639Immune Cell Function and InteractionPluripotent Stem Cells ResearchAnimal Genetics and Reproduction

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

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Gornalusse, Germán G, Hirata, Roli K, Funk, Sarah E, Riolobos, Laura, Lopes, Vanda S, Manske, Gabriel, Prunkard, Donna, Colunga, Aric G +4 more·2017·Nature Biotechnology
DOI 10.1038/nbt.3860PMC PMC5548598
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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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References 53 · Cited by 639

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Authors
Gornalusse, G. G., Hirata, R. K., Funk, S. E., Riolobos, L., Lopes, V. S., Manske, G., Prunkard, D., Colunga, A. G., Hanafi, L.-A., Clegg, D. O., Turtle, C., & Russell, D. W.
Affiliations
  • University of Washington (US)
  • University of California, Santa Barbara (US)
  • Fred Hutch Cancer Center (US)
Corresponding author
Russell, David W
ORCID
Venue
Nature Biotechnology
Publisher
Springer Science and Business Media LLC
Published
2017-05-15
Volume
35
Issue
8
Pages
765-772
ISSN
  • 0733-222X (ISSN-L)
  • 1087-0156
  • 1546-1696
DOI
10.1038/nbt.3860
PMC
PMC5548598
OpenAlex
W2616215756
Cited by
639
References
53
Citations by year
2026: 64 · 2025: 74 · 2024: 79 · 2023: 81 · 2022: 81 · 2021: 71 · 2020: 83 · 2019: 64 · 2018: 35 · 2017: 7
FWCI
23.39
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Biotechnology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL130770, T32HL007093)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK055759, U54DK106829)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Animal Genetics and Reproduction
Keywords
HLA-E, pluripotent stem cells, natural killer cells, allogeneic rejection, beta2-microglobulin, HLA class I, NK cell-mediated lysis, CD8+ T cell recognition, HLA antibodies, HLA class II
MeSH terms
Animals, Female, Graft Rejection, HLA Antigens, Humans, Killer Cells, Natural, Transplants, Pluripotent Stem Cells, Mice

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