Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells

Pablo F. Céspedes, Susan M. Bueno, Bruno A. Ramírez, Roberto S. Gomez, Sebastián A. Riquelme, Christian E. Palavecino, Juan Pablo Mackern-Oberti, Jorge E. Mora, David Depoil, Catarina Sacristań, Michael Cammer, Alison Creneguy, Tuan H. Nguyen, Claudia A. Riedel, Michael L. Dustin, Alexis M. Kalergis

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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.

Idioma originalInglés
Páginas (desde-hasta)E3214-E3223
PublicaciónProceedings of the National Academy of Sciences of the United States of America
EstadoPublicada - 5 ago. 2014

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