MHC Class I Enables MSCs to Evade NK-Cell-Mediated Cytotoxicity and Exert Immunosuppressive Activity

Joo Youn Oh, Hyemee Kim, Hyun Ju Lee, Kangin Lee, Heather Barreda, Hyeon Ji Kim, Eunji Shin, Eun Hye Bae, Gagandeep Kaur, Yu Zhang, Eunjae Kim, Jae Young Lee, Ryang Hwa Lee

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Allogeneic mesenchymal stem/stromal cells (MSCs) are frequently used in clinical trials due to their low expression of major histocompatibility complex (MHC) class I and lack of MHC class II. However, the levels of MHC classes I and II in MSCs are increased by inflammatory stimuli, raising concerns over potential adverse effects associated with allogeneic cell therapy. Also, it is unclear how the host immune response to MHC-mismatched MSCs affects the therapeutic efficacy of the cells. Herein, using strategies to manipulate MHC genes in human bone marrow-derived MSCs via the CRISPR-Cas9 system, plasmids, or siRNAs, we found that inhibition of MHC class I-not MHC class II-in MSCs lowered the survival rate of MSCs and their immunosuppressive potency in mice with experimental autoimmune uveoretinitis, specifically by increasing MSC vulnerability to natural killer (NK)-cell-mediated cytotoxicity. A subsequent survey of MSC batches derived from 6 human donors confirmed a significant correlation between MSC survival rate and susceptibility to NK cells with the potency of MSCs to increase MHC class I level upon stimulation. Our overall results demonstrate that MHC class I enables MSCs to evade NK-cell-mediated cytotoxicity and exert immunosuppressive activity.

Original languageEnglish
Pages (from-to)870-882
Number of pages13
JournalStem Cells
Volume40
Issue number9
DOIs
StatePublished - 26 Sep 2022

Keywords

  • autoimmune disease
  • immunosuppression
  • major histocompatibility complex
  • mesenchymal stem cells
  • mesenchymal stromal cells

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