期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 31, 页码 E3214-E3223出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1400760111
关键词
T lymphocyte priming; nucleocapsid protein; cSMAC; pSMAC
资金
- Fondo Nacional de Desarrollo Cientifico y Tecnologico [3100090, 1070352, 3140455]
- Fondo de Fomento al Desarrollo Cientifico y Tecnologico [D061008]
- Millennium Institute on Immunology and Immunotherapy [P07/088-F]
- Grant Nouvelles Equipes-nouvelles thematiques from the La Region Pays De La Loire
- Evaluation-Orientation of Scientific Cooperation France-Chile Grant
- Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
- Becas Chile scholarship
- Proyecto de Insercion de Capital Humano en la Academia from CONICYT [79100015]
- National Institutes of Health [AI043542, AI080192]
- Wellcome Trust
- Kennedy Trust
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 naive 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.
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