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Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells
Siglec-9 is an MHC-independent inhibitory receptor expressed on a subset of natural killer (NK) cells. Siglec-9 restrains NK cytotoxicity by binding to sialoglycans (sialic acid-containing glycans) on target cells. Despite the importance of Siglec-9 interactions in tumor immune evasion, their role a...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584986/ https://www.ncbi.nlm.nih.gov/pubmed/34762717 http://dx.doi.org/10.1371/journal.ppat.1010034 |
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author | Adeniji, Opeyemi S. Kuri-Cervantes, Leticia Yu, Chenfei Xu, Ziyang Ho, Michelle Chew, Glen M. Shikuma, Cecilia Tomescu, Costin George, Ashley F. Roan, Nadia R. Ndhlovu, Lishomwa C. Liu, Qin Muthumani, Kar Weiner, David B. Betts, Michael R. Xiao, Han Abdel-Mohsen, Mohamed |
author_facet | Adeniji, Opeyemi S. Kuri-Cervantes, Leticia Yu, Chenfei Xu, Ziyang Ho, Michelle Chew, Glen M. Shikuma, Cecilia Tomescu, Costin George, Ashley F. Roan, Nadia R. Ndhlovu, Lishomwa C. Liu, Qin Muthumani, Kar Weiner, David B. Betts, Michael R. Xiao, Han Abdel-Mohsen, Mohamed |
author_sort | Adeniji, Opeyemi S. |
collection | PubMed |
description | Siglec-9 is an MHC-independent inhibitory receptor expressed on a subset of natural killer (NK) cells. Siglec-9 restrains NK cytotoxicity by binding to sialoglycans (sialic acid-containing glycans) on target cells. Despite the importance of Siglec-9 interactions in tumor immune evasion, their role as an immune evasion mechanism during HIV infection has not been investigated. Using in vivo phenotypic analyses, we found that Siglec-9(+) CD56(dim) NK cells, during HIV infection, exhibit an activated phenotype with higher expression of activating receptors and markers (NKp30, CD38, CD16, DNAM-1, perforin) and lower expression of the inhibitory receptor NKG2A, compared to Siglec-9(-) CD56(dim) NK cells. We also found that levels of Siglec-9(+) CD56(dim) NK cells inversely correlate with viral load during viremic infection and CD4(+) T cell-associated HIV DNA during suppressed infection. Using in vitro cytotoxicity assays, we confirmed that Siglec-9(+) NK cells exhibit higher cytotoxicity towards HIV-infected cells compared to Siglec-9(-) NK cells. These data are consistent with the notion that Siglec-9(+) NK cells are highly cytotoxic against HIV-infected cells. However, blocking Siglec-9 enhanced NK cells’ ability to lyse HIV-infected cells, consistent with the known inhibitory function of the Siglec-9 molecule. Together, these data support a model in which the Siglec-9(+) CD56(dim) NK subpopulation is highly cytotoxic against HIV-infected cells even whilst being restrained by the inhibitory effects of Siglec-9. To harness the cytotoxic capacity of the Siglec-9(+) NK subpopulation, which is dampened by Siglec-9, we developed a proof-of-concept approach to selectively disrupt Siglec/sialoglycan interactions between NK and HIV-infected cells. We achieved this goal by conjugating Sialidase to several HIV broadly neutralizing antibodies. These conjugates selectively desialylated HIV-infected cells and enhanced NK cells’ capacity to kill them. In summary, we identified a novel, glycan-based interaction that may contribute to HIV-infected cells’ ability to evade NK immunosurveillance and developed an approach to break this interaction. |
format | Online Article Text |
id | pubmed-8584986 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-85849862021-11-12 Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells Adeniji, Opeyemi S. Kuri-Cervantes, Leticia Yu, Chenfei Xu, Ziyang Ho, Michelle Chew, Glen M. Shikuma, Cecilia Tomescu, Costin George, Ashley F. Roan, Nadia R. Ndhlovu, Lishomwa C. Liu, Qin Muthumani, Kar Weiner, David B. Betts, Michael R. Xiao, Han Abdel-Mohsen, Mohamed PLoS Pathog Research Article Siglec-9 is an MHC-independent inhibitory receptor expressed on a subset of natural killer (NK) cells. Siglec-9 restrains NK cytotoxicity by binding to sialoglycans (sialic acid-containing glycans) on target cells. Despite the importance of Siglec-9 interactions in tumor immune evasion, their role as an immune evasion mechanism during HIV infection has not been investigated. Using in vivo phenotypic analyses, we found that Siglec-9(+) CD56(dim) NK cells, during HIV infection, exhibit an activated phenotype with higher expression of activating receptors and markers (NKp30, CD38, CD16, DNAM-1, perforin) and lower expression of the inhibitory receptor NKG2A, compared to Siglec-9(-) CD56(dim) NK cells. We also found that levels of Siglec-9(+) CD56(dim) NK cells inversely correlate with viral load during viremic infection and CD4(+) T cell-associated HIV DNA during suppressed infection. Using in vitro cytotoxicity assays, we confirmed that Siglec-9(+) NK cells exhibit higher cytotoxicity towards HIV-infected cells compared to Siglec-9(-) NK cells. These data are consistent with the notion that Siglec-9(+) NK cells are highly cytotoxic against HIV-infected cells. However, blocking Siglec-9 enhanced NK cells’ ability to lyse HIV-infected cells, consistent with the known inhibitory function of the Siglec-9 molecule. Together, these data support a model in which the Siglec-9(+) CD56(dim) NK subpopulation is highly cytotoxic against HIV-infected cells even whilst being restrained by the inhibitory effects of Siglec-9. To harness the cytotoxic capacity of the Siglec-9(+) NK subpopulation, which is dampened by Siglec-9, we developed a proof-of-concept approach to selectively disrupt Siglec/sialoglycan interactions between NK and HIV-infected cells. We achieved this goal by conjugating Sialidase to several HIV broadly neutralizing antibodies. These conjugates selectively desialylated HIV-infected cells and enhanced NK cells’ capacity to kill them. In summary, we identified a novel, glycan-based interaction that may contribute to HIV-infected cells’ ability to evade NK immunosurveillance and developed an approach to break this interaction. Public Library of Science 2021-11-11 /pmc/articles/PMC8584986/ /pubmed/34762717 http://dx.doi.org/10.1371/journal.ppat.1010034 Text en © 2021 Adeniji et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Adeniji, Opeyemi S. Kuri-Cervantes, Leticia Yu, Chenfei Xu, Ziyang Ho, Michelle Chew, Glen M. Shikuma, Cecilia Tomescu, Costin George, Ashley F. Roan, Nadia R. Ndhlovu, Lishomwa C. Liu, Qin Muthumani, Kar Weiner, David B. Betts, Michael R. Xiao, Han Abdel-Mohsen, Mohamed Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells |
title | Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells |
title_full | Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells |
title_fullStr | Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells |
title_full_unstemmed | Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells |
title_short | Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells |
title_sort | siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to hiv-infected cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584986/ https://www.ncbi.nlm.nih.gov/pubmed/34762717 http://dx.doi.org/10.1371/journal.ppat.1010034 |
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