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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-11-01
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| Series: | PLoS Pathogens |
| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584986/?tool=EBI |
| _version_ | 1818750732459835392 |
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| 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 |
| collection | DOAJ |
| 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. Author summary The Siglec-9 molecule, expressed on NK cells, binds to Sialic acid, expressed on target cells, and this binding induces an inhibitory signal to NK cells. As such, Siglec-9 functions as a “glyco-immune negative checkpoint”. Despite the importance of such Siglec-9-Sialoglycan interactions in tumor immune evasion, their role as an immune evasion mechanism during HIV infection has not been investigated. We found that the cytotoxicity of the Siglec-9+ CD56dim NK subpopulation against HIV-infected cells is indeed being restrained by the inhibitory nature of the Siglec-9 molecule itself. However, we also found that this Siglec-9+ CD56dim NK subpopulation is highly cytotoxic against HIV-infected cells compared to the Siglec-9- CD56dim NK subpopulation. Our data suggest that Siglec-9 is expressed on highly cytotoxic NK cells, where it restrains their high cytotoxicity. We have also developed a proof-of-concept immunotherapy approach to selectively disrupt Siglec/sialoglycan interactions between NK cells and HIV-infected cells. We did so by conjugating Sialidase to HIV broadly neutralizing antibodies. These conjugates selectively desialylated HIV-infected cells and enhanced NK capacity to kill infected cells. Our findings bring to light the potentially relevant and previously unrecognized glyco-immune checkpoint mechanisms that may contribute to the ability of HIV-infected cells to evade host immunosurveillance. |
| first_indexed | 2024-12-18T04:24:21Z |
| format | Article |
| id | doaj.art-db11dfbb65534cb3924abe59420fa723 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-18T04:24:21Z |
| publishDate | 2021-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-db11dfbb65534cb3924abe59420fa7232022-12-21T21:21:09ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742021-11-011711Siglec-9 defines and restrains a natural killer subpopulation highly cytotoxic to HIV-infected cellsOpeyemi 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-MohsenSiglec-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. Author summary The Siglec-9 molecule, expressed on NK cells, binds to Sialic acid, expressed on target cells, and this binding induces an inhibitory signal to NK cells. As such, Siglec-9 functions as a “glyco-immune negative checkpoint”. Despite the importance of such Siglec-9-Sialoglycan interactions in tumor immune evasion, their role as an immune evasion mechanism during HIV infection has not been investigated. We found that the cytotoxicity of the Siglec-9+ CD56dim NK subpopulation against HIV-infected cells is indeed being restrained by the inhibitory nature of the Siglec-9 molecule itself. However, we also found that this Siglec-9+ CD56dim NK subpopulation is highly cytotoxic against HIV-infected cells compared to the Siglec-9- CD56dim NK subpopulation. Our data suggest that Siglec-9 is expressed on highly cytotoxic NK cells, where it restrains their high cytotoxicity. We have also developed a proof-of-concept immunotherapy approach to selectively disrupt Siglec/sialoglycan interactions between NK cells and HIV-infected cells. We did so by conjugating Sialidase to HIV broadly neutralizing antibodies. These conjugates selectively desialylated HIV-infected cells and enhanced NK capacity to kill infected cells. Our findings bring to light the potentially relevant and previously unrecognized glyco-immune checkpoint mechanisms that may contribute to the ability of HIV-infected cells to evade host immunosurveillance.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584986/?tool=EBI |
| spellingShingle | 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 PLoS Pathogens |
| 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 |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584986/?tool=EBI |
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