Abstract
We previously reported a method to generate dendritic cell (DC)-like antigen-presenting cells (APC) from human induced pluripotent stem (iPS) cells. However, the method is relatively complicated and laborious. In the current study, we attempted to establish a method through which we could obtain a large number of functional APC with a simple procedure. We transduced iPS cell-derived CD11b+ myeloid cells with genes associated with proliferative or anti-senescence effects, enabling the cells to propagate for more than 4 months in a macrophage colony-stimulating factor (M-CSF)-dependent manner while retaining their capacity to differentiate into functional APC. We named these iPS cell-derived proliferating myeloid cells ‘iPS-ML’, and the iPS-ML-derived APC ‘ML-DC’. In addition, we generated TAP2-deficient iPS cell clones by zinc finger nuclease-aided targeted gene disruption. TAP2-deficient iPS cells and iPS-ML avoided recognition by pre-activated allo-reactive CD8+ T cells. TAP2-deficient ML-DC expressing exogenously introduced HLA-A2 genes stimulated HLA-A2-restricted MART-1-specific CD8+ T cells obtained from HLA-A2-positive allogeneic donors, resulting in generation of MART-1-specific cytotoxic T lymphocyte (CTL) lines. TAP-deficient iPS-ML introduced with various HLA class I genes may serve as an unlimited source of APC for vaccination therapy. If administered into allogeneic patients, ML-DC with appropriate genetic modifications may survive long enough to stimulate antigen-specific CTL and, after that, be completely eliminated. Based on the present study, we propose an APC-producing system that is simple, safe and applicable to all patients irrespective of their HLA types.
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Abbreviations
- APC:
-
antigen-presenting cells
- DC:
-
dendritic cells
- ES cell:
-
embryonic stem cell
- iPS cell:
-
induced pluripotent stem cell
- iPS-MC:
-
iPS cell-derived myeloid cells
- iPS-ML:
-
iPS cell-derived myeloid cell line
- ML-DC:
-
iPS-ML-derived dendritic cell-like APC.
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Acknowledgements
The cDNA clones for MDM2, BMI1, and EZH2 and 293T cells were provided by RIKEN BRC, which is participating in the National Bio-Resources Project of the MEXT, Japan. The pCSII-EF, pCMV-VSV-G-RSV-Rev and pCAG-HIVgp constructs were kindly provided by Dr H Miyoshi (RIKEN BioResource Center). This work was supported in part by Grants-in-Aid Nos 18014023, 19591172 and 19059012 from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan, Research Grant for Intractable Diseases from Ministry of Health and Welfare, Japan and grants from Japan Science and Technology Agency (JST).
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Haruta, M., Tomita, Y., Yuno, A. et al. TAP-deficient human iPS cell-derived myeloid cell lines as unlimited cell source for dendritic cell-like antigen-presenting cells. Gene Ther 20, 504–513 (2013). https://doi.org/10.1038/gt.2012.59
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DOI: https://doi.org/10.1038/gt.2012.59
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