Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells.
Human respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in young children worldwide. The recurrent hRSV outbreaks and reinfections are the cause of a significant public health burden and associate with an inefficient antiviral immunity, even after disease resolut...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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National Academy of Sciences
2014
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| _version_ | 1797101584496197632 |
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| author | Céspedes, P Bueno, S Ramírez, B Gomez, R Riquelme, SA Palavecino, C Mackern-Oberti, J Mora, J Depoil, D Sacristán, C Cammer, M Creneguy, A Nguyen, T Riedel, C Dustin, M Kalergis, A |
| author_facet | Céspedes, P Bueno, S Ramírez, B Gomez, R Riquelme, SA Palavecino, C Mackern-Oberti, J Mora, J Depoil, D Sacristán, C Cammer, M Creneguy, A Nguyen, T Riedel, C Dustin, M Kalergis, A |
| author_sort | Céspedes, P |
| collection | OXFORD |
| description | Human respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in young children worldwide. The recurrent hRSV outbreaks and reinfections are the cause of a significant public health burden and associate with an inefficient antiviral immunity, even after disease resolution. Although several mouse- and human cell-based studies have shown that hRSV infection prevents naïve T-cell activation by antigen-presenting cells, the mechanism underlying such inhibition remains unknown. Here, we show that the hRSV nucleoprotein (N) could be at least partially responsible for inhibiting T-cell activation during infection by this virus. Early after infection, the N protein was expressed on the surface of epithelial and dendritic cells, after interacting with trans-Golgi and lysosomal compartments. Further, experiments on supported lipid bilayers loaded with peptide-MHC (pMHC) complexes showed that surface-anchored N protein prevented immunological synapse assembly by naive CD4(+) T cells and, to a lesser extent, by antigen-experienced T-cell blasts. Synapse assembly inhibition was in part due to reduced T-cell receptor (TCR) signaling and pMHC clustering at the T-cell-bilayer interface, suggesting that N protein interferes with pMHC-TCR interactions. Moreover, N protein colocalized with the TCR independently of pMHC, consistent with a possible interaction with TCR complex components. Based on these data, we conclude that hRSV N protein expression at the surface of infected cells inhibits T-cell activation. Our study defines this protein as a major virulence factor that contributes to impairing acquired immunity and enhances susceptibility to reinfection by hRSV. |
| first_indexed | 2024-03-07T05:53:56Z |
| format | Journal article |
| id | oxford-uuid:e9dde145-77f0-4b2d-9ddf-c1588eb3451a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:53:56Z |
| publishDate | 2014 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | oxford-uuid:e9dde145-77f0-4b2d-9ddf-c1588eb3451a2022-03-27T10:57:23ZSurface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e9dde145-77f0-4b2d-9ddf-c1588eb3451aEnglishSymplectic Elements at OxfordNational Academy of Sciences2014Céspedes, PBueno, SRamírez, BGomez, RRiquelme, SAPalavecino, CMackern-Oberti, JMora, JDepoil, DSacristán, CCammer, MCreneguy, ANguyen, TRiedel, CDustin, MKalergis, AHuman respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in young children worldwide. The recurrent hRSV outbreaks and reinfections are the cause of a significant public health burden and associate with an inefficient antiviral immunity, even after disease resolution. Although several mouse- and human cell-based studies have shown that hRSV infection prevents naïve T-cell activation by antigen-presenting cells, the mechanism underlying such inhibition remains unknown. Here, we show that the hRSV nucleoprotein (N) could be at least partially responsible for inhibiting T-cell activation during infection by this virus. Early after infection, the N protein was expressed on the surface of epithelial and dendritic cells, after interacting with trans-Golgi and lysosomal compartments. Further, experiments on supported lipid bilayers loaded with peptide-MHC (pMHC) complexes showed that surface-anchored N protein prevented immunological synapse assembly by naive CD4(+) T cells and, to a lesser extent, by antigen-experienced T-cell blasts. Synapse assembly inhibition was in part due to reduced T-cell receptor (TCR) signaling and pMHC clustering at the T-cell-bilayer interface, suggesting that N protein interferes with pMHC-TCR interactions. Moreover, N protein colocalized with the TCR independently of pMHC, consistent with a possible interaction with TCR complex components. Based on these data, we conclude that hRSV N protein expression at the surface of infected cells inhibits T-cell activation. Our study defines this protein as a major virulence factor that contributes to impairing acquired immunity and enhances susceptibility to reinfection by hRSV. |
| spellingShingle | Céspedes, P Bueno, S Ramírez, B Gomez, R Riquelme, SA Palavecino, C Mackern-Oberti, J Mora, J Depoil, D Sacristán, C Cammer, M Creneguy, A Nguyen, T Riedel, C Dustin, M Kalergis, A Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. |
| title | Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. |
| title_full | Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. |
| title_fullStr | Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. |
| title_full_unstemmed | Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. |
| title_short | Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells. |
| title_sort | surface expression of the hrsv nucleoprotein impairs immunological synapse formation with t cells |
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