The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype
Circulating natural killer (NK) cells have been shown to adopt a type 1 innate lymphoid cell (ILC1)-like phenotype in response to TGF-β and secrete VEGF-A when exposed to hypoxia. Although these changes are often considered to be linked attributes of tissue residency, it has yet to be determined if...
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| Format: | Article |
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.01903/full |
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| author | Lindsey G. Hawke Mara K. M. Whitford Mark L. Ormiston Mark L. Ormiston |
| author_facet | Lindsey G. Hawke Mara K. M. Whitford Mark L. Ormiston Mark L. Ormiston |
| author_sort | Lindsey G. Hawke |
| collection | DOAJ |
| description | Circulating natural killer (NK) cells have been shown to adopt a type 1 innate lymphoid cell (ILC1)-like phenotype in response to TGF-β and secrete VEGF-A when exposed to hypoxia. Although these changes are often considered to be linked attributes of tissue residency, it has yet to be determined if TGF-β and hypoxia work in concert to coordinate NK cellular phenotype and angiogenic potential. Examination of human circulating NK cells treated with TGF-β demonstrated heterogeneity in their potential to adopt an ILC1-like phenotype, as indicated by the upregulation of CD9 and CD103 on only a subset of cells in culture. Culturing NK cells in chronic hypoxia did not induce a similar ILC1-like conversion and did not enhance the degree of conversion for cells exposed to TGF-β. Similarly, hypoxic culture of circulating NK cells induced VEGF-A secretion, but this production was not enhanced by TGF-β. Fluorescent in-situ hybridization flow cytometry demonstrated that hypoxia-induced VEGF-A production was uniform across all NK cells in culture and was not a selective feature of the cellular subset that adopted an ILC1-like phenotype in response to TGF-β. Examination of VEGF-A isoforms demonstrated that hypoxia induces the production of pro-angiogenic VEGF-A isoforms, including VEGF-A165 and VEGF-A121, and does not stimulate any meaningful production of anti-angiogenic isoforms, such as VEGF-Ab transcriptional variants or VEGF-Ax. In summary, TGF-β-mediated ILC1-like conversion and hypoxia-induced VEGF-A production are discrete processes in NK cells and are not part of a linked cellular program associated with tissue residency. |
| first_indexed | 2024-12-10T07:17:45Z |
| format | Article |
| id | doaj.art-21067a35b58349cc8a944a4d96cbb83a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T07:17:45Z |
| publishDate | 2020-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-21067a35b58349cc8a944a4d96cbb83a2022-12-22T01:57:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-08-011110.3389/fimmu.2020.01903569341The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like PhenotypeLindsey G. Hawke0Mara K. M. Whitford1Mark L. Ormiston2Mark L. Ormiston3Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, CanadaDepartment of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, CanadaDepartment of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, CanadaDepartment of Medicine, Queen's University, Kingston, ON, CanadaCirculating natural killer (NK) cells have been shown to adopt a type 1 innate lymphoid cell (ILC1)-like phenotype in response to TGF-β and secrete VEGF-A when exposed to hypoxia. Although these changes are often considered to be linked attributes of tissue residency, it has yet to be determined if TGF-β and hypoxia work in concert to coordinate NK cellular phenotype and angiogenic potential. Examination of human circulating NK cells treated with TGF-β demonstrated heterogeneity in their potential to adopt an ILC1-like phenotype, as indicated by the upregulation of CD9 and CD103 on only a subset of cells in culture. Culturing NK cells in chronic hypoxia did not induce a similar ILC1-like conversion and did not enhance the degree of conversion for cells exposed to TGF-β. Similarly, hypoxic culture of circulating NK cells induced VEGF-A secretion, but this production was not enhanced by TGF-β. Fluorescent in-situ hybridization flow cytometry demonstrated that hypoxia-induced VEGF-A production was uniform across all NK cells in culture and was not a selective feature of the cellular subset that adopted an ILC1-like phenotype in response to TGF-β. Examination of VEGF-A isoforms demonstrated that hypoxia induces the production of pro-angiogenic VEGF-A isoforms, including VEGF-A165 and VEGF-A121, and does not stimulate any meaningful production of anti-angiogenic isoforms, such as VEGF-Ab transcriptional variants or VEGF-Ax. In summary, TGF-β-mediated ILC1-like conversion and hypoxia-induced VEGF-A production are discrete processes in NK cells and are not part of a linked cellular program associated with tissue residency.https://www.frontiersin.org/article/10.3389/fimmu.2020.01903/fullnatural killer cellstransforming growth factor-βvascular endothelial growth factor-Aangiogenesistissue residency |
| spellingShingle | Lindsey G. Hawke Mara K. M. Whitford Mark L. Ormiston Mark L. Ormiston The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype Frontiers in Immunology natural killer cells transforming growth factor-β vascular endothelial growth factor-A angiogenesis tissue residency |
| title | The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype |
| title_full | The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype |
| title_fullStr | The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype |
| title_full_unstemmed | The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype |
| title_short | The Production of Pro-angiogenic VEGF-A Isoforms by Hypoxic Human NK Cells Is Independent of Their TGF-β-Mediated Conversion to an ILC1-Like Phenotype |
| title_sort | production of pro angiogenic vegf a isoforms by hypoxic human nk cells is independent of their tgf β mediated conversion to an ilc1 like phenotype |
| topic | natural killer cells transforming growth factor-β vascular endothelial growth factor-A angiogenesis tissue residency |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.01903/full |
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