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...

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Autores principales:	Opeyemi S Adeniji, Leticia Kuri-Cervantes, Chenfei Yu, Ziyang Xu, Michelle Ho, Glen M Chew, Cecilia Shikuma, Costin Tomescu, Ashley F George, Nadia R Roan, Lishomwa C Ndhlovu, Qin Liu, Kar Muthumani, David B Weiner, Michael R Betts, Han Xiao, Mohamed Abdel-Mohsen
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7893d0635c944c17b3235ba1b247de02
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spelling	oai:doaj.org-article:7893d0635c944c17b3235ba1b247de022021-12-02T19:59:52ZSiglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells.1553-73661553-737410.1371/journal.ppat.1010034https://doaj.org/article/7893d0635c944c17b3235ba1b247de022021-11-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1010034https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Siglec-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+ CD56dim 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- CD56dim NK cells. We also found that levels of Siglec-9+ CD56dim 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+ CD56dim 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.Opeyemi S AdenijiLeticia Kuri-CervantesChenfei YuZiyang XuMichelle HoGlen M ChewCecilia ShikumaCostin TomescuAshley F GeorgeNadia R RoanLishomwa C NdhlovuQin LiuKar MuthumaniDavid B WeinerMichael R BettsHan XiaoMohamed Abdel-MohsenPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 17, Iss 11, p e1010034 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Opeyemi S Adeniji Leticia Kuri-Cervantes Chenfei Yu Ziyang Xu Michelle Ho Glen M Chew Cecilia Shikuma Costin Tomescu Ashley F George Nadia R Roan Lishomwa C Ndhlovu Qin Liu Kar Muthumani David B Weiner Michael R Betts Han Xiao Mohamed Abdel-Mohsen Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells.
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+ CD56dim 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- CD56dim NK cells. We also found that levels of Siglec-9+ CD56dim 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+ CD56dim 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	article
author	Opeyemi S Adeniji Leticia Kuri-Cervantes Chenfei Yu Ziyang Xu Michelle Ho Glen M Chew Cecilia Shikuma Costin Tomescu Ashley F George Nadia R Roan Lishomwa C Ndhlovu Qin Liu Kar Muthumani David B Weiner Michael R Betts Han Xiao Mohamed Abdel-Mohsen
author_facet	Opeyemi S Adeniji Leticia Kuri-Cervantes Chenfei Yu Ziyang Xu Michelle Ho Glen M Chew Cecilia Shikuma Costin Tomescu Ashley F George Nadia R Roan Lishomwa C Ndhlovu Qin Liu Kar Muthumani David B Weiner Michael R Betts Han Xiao Mohamed Abdel-Mohsen
author_sort	Opeyemi S Adeniji
title	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_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_sort	siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to hiv-infected cells.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/7893d0635c944c17b3235ba1b247de02
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Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cells.

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