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Natural Killer Cell Inhibition by HLA-E Molecules on Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelial Cells.
Invest Ophthalmol Vis Sci. 2018 04 01; 59(5):1719-1731.IO

Abstract

Purpose

To determine whether human induced pluripotent stem (iPS) cell-derived retinal pigment epithelial (RPE) cells (iPS-RPE) can suppress natural killer (NK) cell activation.

Methods

iPS-RPE cells were cocultured with peripheral blood mononuclear cells (PBMCs) or purified NK cells from healthy donors after stimulation with cytokines. To confirm expression of NK cell-specific markers, flow cytometry and quantitative RT-PCR (qRT-PCR) were performed. NK cells (or PBMCs) cocultured with iPS-RPE cells were assessed for proliferation by Ki-67 expression with flow cytometry, and NK suppression by RPE cells was assessed for granzyme B production with ELISA. Human leukocyte antigen (HLA) expression including HLA-E on iPS-RPE cells was evaluated with flow cytometry and qRT-PCR. The effect of HLA-E downregulation was also investigated using small interfering RNA (siRNA) systems. Following iPS-RPE cell transplantation in vivo, we evaluated NK cell invasion in the retina with immunohistochemistry.

Results

Activated NK cells expressed NK-related markers such as CD16, CD56, and CD11b, and NK cells produced cytotoxic agents such as granzyme B, perforin, and TNF-α. Human iPS-RPE cells inhibited cell proliferation and production of these cytotoxic agents by activated NK cells in vitro. iPS-RPE cells constitutively expressed HLA-E and suppressed NK cell activation through an interaction between HLA-E and CD94/NKG2A. Moreover, immunohistochemical evaluation of monkey RPE transplantation into in vivo immune rejection models showed no NK cell invasion in the retina in allografts or xenografts except for one xenografted eye.

Conclusions

Cultured iPS cell-derived RPE cells greatly suppress NK cell activation. Thus, NK cells might be inactivated when exposed to this type of retinal cell.

Authors+Show Affiliations

Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan.Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan.Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan. Department of Ophthalmology & Visual Science, Tokyo Medical and Dental University Graduate School of Medicine and Dental Sciences, Tokyo, Japan.Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan. Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, Hyogo, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29610856

Citation

Sugita, Sunao, et al. "Natural Killer Cell Inhibition By HLA-E Molecules On Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelial Cells." Investigative Ophthalmology & Visual Science, vol. 59, no. 5, 2018, pp. 1719-1731.
Sugita S, Makabe K, Iwasaki Y, et al. Natural Killer Cell Inhibition by HLA-E Molecules on Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelial Cells. Invest Ophthalmol Vis Sci. 2018;59(5):1719-1731.
Sugita, S., Makabe, K., Iwasaki, Y., Fujii, S., & Takahashi, M. (2018). Natural Killer Cell Inhibition by HLA-E Molecules on Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelial Cells. Investigative Ophthalmology & Visual Science, 59(5), 1719-1731. https://doi.org/10.1167/iovs.17-22703
Sugita S, et al. Natural Killer Cell Inhibition By HLA-E Molecules On Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelial Cells. Invest Ophthalmol Vis Sci. 2018 04 1;59(5):1719-1731. PubMed PMID: 29610856.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Natural Killer Cell Inhibition by HLA-E Molecules on Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelial Cells. AU - Sugita,Sunao, AU - Makabe,Kenichi, AU - Iwasaki,Yuko, AU - Fujii,Shota, AU - Takahashi,Masayo, PY - 2018/4/4/entrez PY - 2018/4/4/pubmed PY - 2019/1/29/medline SP - 1719 EP - 1731 JF - Investigative ophthalmology & visual science JO - Invest Ophthalmol Vis Sci VL - 59 IS - 5 N2 - Purpose: To determine whether human induced pluripotent stem (iPS) cell-derived retinal pigment epithelial (RPE) cells (iPS-RPE) can suppress natural killer (NK) cell activation. Methods: iPS-RPE cells were cocultured with peripheral blood mononuclear cells (PBMCs) or purified NK cells from healthy donors after stimulation with cytokines. To confirm expression of NK cell-specific markers, flow cytometry and quantitative RT-PCR (qRT-PCR) were performed. NK cells (or PBMCs) cocultured with iPS-RPE cells were assessed for proliferation by Ki-67 expression with flow cytometry, and NK suppression by RPE cells was assessed for granzyme B production with ELISA. Human leukocyte antigen (HLA) expression including HLA-E on iPS-RPE cells was evaluated with flow cytometry and qRT-PCR. The effect of HLA-E downregulation was also investigated using small interfering RNA (siRNA) systems. Following iPS-RPE cell transplantation in vivo, we evaluated NK cell invasion in the retina with immunohistochemistry. Results: Activated NK cells expressed NK-related markers such as CD16, CD56, and CD11b, and NK cells produced cytotoxic agents such as granzyme B, perforin, and TNF-α. Human iPS-RPE cells inhibited cell proliferation and production of these cytotoxic agents by activated NK cells in vitro. iPS-RPE cells constitutively expressed HLA-E and suppressed NK cell activation through an interaction between HLA-E and CD94/NKG2A. Moreover, immunohistochemical evaluation of monkey RPE transplantation into in vivo immune rejection models showed no NK cell invasion in the retina in allografts or xenografts except for one xenografted eye. Conclusions: Cultured iPS cell-derived RPE cells greatly suppress NK cell activation. Thus, NK cells might be inactivated when exposed to this type of retinal cell. SN - 1552-5783 UR - https://www.unboundmedicine.com/medline/citation/29610856/Natural_Killer_Cell_Inhibition_by_HLA_E_Molecules_on_Induced_Pluripotent_Stem_Cell_Derived_Retinal_Pigment_Epithelial_Cells_ L2 - https://iovs.arvojournals.org/article.aspx?doi=10.1167/iovs.17-22703 DB - PRIME DP - Unbound Medicine ER -