Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response

Shirin Munir, Philippa Hillyer, Cyril le Nouën, Ursula J. Buchholz, Ronald L. Rabin, Peter L. Collins, Alexander Bukreyev

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

We recently demonstrated that the respiratory syncytial virus (RSV) NS1 protein, an antagonist of host type I interferon (IFN-I) production and signaling, has a suppressive effect on the maturation of human dendritic cells (DC) that was only partly dependent on released IFN-I. Here we investigated whether NS1 affects the ability of DC to activate CD8+ and CD4+ T cells. Human DC were infected with RSV deletion mutants lacking the NS1 and/or NS2 genes and assayed for the ability to activate autologous T cells in vitro, which were analyzed by multi-color flow cytometry. Deletion of the NS1, but not NS2, protein resulted in three major effects: (i) an increased activation and proliferation of CD8+ T cells that express CD103, a tissue homing integrin that directs CD8+ T cells to mucosal epithelial cells of the respiratory tract and triggers cytolytic activity; (ii) an increased activation and proliferation of Th17 cells, which have recently been shown to have anti-viral effects and also indirectly attract neutrophils; and (iii) decreased activation of IL-4-producing CD4+ T cells - which are associated with enhanced RSV disease - and reduced proliferation of total CD4+ T cells. Except for total CD4+ T cell proliferation, none of the T cell effects appeared to be due to increased IFN-I signaling. In the infected DC, deletion of the NS1 and NS2 genes strongly up-regulated the expression of cytokines and other molecules involved in DC maturation. This was partly IFN-I-independent, and thus might account for the T cell effects. Taken together, these data demonstrate that the NS1 protein suppresses proliferation and activation of two of the protective cell populations (CD103+ CD8+ T cells and Th17 cells), and promotes proliferation and activation of Th2 cells that can enhance RSV disease.

Original languageEnglish (US)
Article numbere1001336
JournalPLoS Pathogens
Volume7
Issue number4
DOIs
StatePublished - Apr 2011

Fingerprint

Respiratory Syncytial Viruses
Interferons
T-Lymphocytes
Dendritic Cells
Proteins
Th17 Cells
Virus Diseases
Cell Proliferation
Interferon Type I
Th2 Cells
Integrins
Interleukin-4
Respiratory System
Genes
Flow Cytometry
Neutrophils
Color
Epithelial Cells
Cytokines

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response. / Munir, Shirin; Hillyer, Philippa; le Nouën, Cyril; Buchholz, Ursula J.; Rabin, Ronald L.; Collins, Peter L.; Bukreyev, Alexander.

In: PLoS Pathogens, Vol. 7, No. 4, e1001336, 04.2011.

Research output: Contribution to journalArticle

Munir, Shirin ; Hillyer, Philippa ; le Nouën, Cyril ; Buchholz, Ursula J. ; Rabin, Ronald L. ; Collins, Peter L. ; Bukreyev, Alexander. / Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response. In: PLoS Pathogens. 2011 ; Vol. 7, No. 4.
@article{e16cadbe577143738f46503e1c740a60,
title = "Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response",
abstract = "We recently demonstrated that the respiratory syncytial virus (RSV) NS1 protein, an antagonist of host type I interferon (IFN-I) production and signaling, has a suppressive effect on the maturation of human dendritic cells (DC) that was only partly dependent on released IFN-I. Here we investigated whether NS1 affects the ability of DC to activate CD8+ and CD4+ T cells. Human DC were infected with RSV deletion mutants lacking the NS1 and/or NS2 genes and assayed for the ability to activate autologous T cells in vitro, which were analyzed by multi-color flow cytometry. Deletion of the NS1, but not NS2, protein resulted in three major effects: (i) an increased activation and proliferation of CD8+ T cells that express CD103, a tissue homing integrin that directs CD8+ T cells to mucosal epithelial cells of the respiratory tract and triggers cytolytic activity; (ii) an increased activation and proliferation of Th17 cells, which have recently been shown to have anti-viral effects and also indirectly attract neutrophils; and (iii) decreased activation of IL-4-producing CD4+ T cells - which are associated with enhanced RSV disease - and reduced proliferation of total CD4+ T cells. Except for total CD4+ T cell proliferation, none of the T cell effects appeared to be due to increased IFN-I signaling. In the infected DC, deletion of the NS1 and NS2 genes strongly up-regulated the expression of cytokines and other molecules involved in DC maturation. This was partly IFN-I-independent, and thus might account for the T cell effects. Taken together, these data demonstrate that the NS1 protein suppresses proliferation and activation of two of the protective cell populations (CD103+ CD8+ T cells and Th17 cells), and promotes proliferation and activation of Th2 cells that can enhance RSV disease.",
author = "Shirin Munir and Philippa Hillyer and {le Nou{\"e}n}, Cyril and Buchholz, {Ursula J.} and Rabin, {Ronald L.} and Collins, {Peter L.} and Alexander Bukreyev",
year = "2011",
month = "4",
doi = "10.1371/journal.ppat.1001336",
language = "English (US)",
volume = "7",
journal = "PLoS Pathogens",
issn = "1553-7366",
publisher = "Public Library of Science",
number = "4",

}

TY - JOUR

T1 - Respiratory syncytial virus interferon antagonist NS1 protein suppresses and skews the human T lymphocyte response

AU - Munir, Shirin

AU - Hillyer, Philippa

AU - le Nouën, Cyril

AU - Buchholz, Ursula J.

AU - Rabin, Ronald L.

AU - Collins, Peter L.

AU - Bukreyev, Alexander

PY - 2011/4

Y1 - 2011/4

N2 - We recently demonstrated that the respiratory syncytial virus (RSV) NS1 protein, an antagonist of host type I interferon (IFN-I) production and signaling, has a suppressive effect on the maturation of human dendritic cells (DC) that was only partly dependent on released IFN-I. Here we investigated whether NS1 affects the ability of DC to activate CD8+ and CD4+ T cells. Human DC were infected with RSV deletion mutants lacking the NS1 and/or NS2 genes and assayed for the ability to activate autologous T cells in vitro, which were analyzed by multi-color flow cytometry. Deletion of the NS1, but not NS2, protein resulted in three major effects: (i) an increased activation and proliferation of CD8+ T cells that express CD103, a tissue homing integrin that directs CD8+ T cells to mucosal epithelial cells of the respiratory tract and triggers cytolytic activity; (ii) an increased activation and proliferation of Th17 cells, which have recently been shown to have anti-viral effects and also indirectly attract neutrophils; and (iii) decreased activation of IL-4-producing CD4+ T cells - which are associated with enhanced RSV disease - and reduced proliferation of total CD4+ T cells. Except for total CD4+ T cell proliferation, none of the T cell effects appeared to be due to increased IFN-I signaling. In the infected DC, deletion of the NS1 and NS2 genes strongly up-regulated the expression of cytokines and other molecules involved in DC maturation. This was partly IFN-I-independent, and thus might account for the T cell effects. Taken together, these data demonstrate that the NS1 protein suppresses proliferation and activation of two of the protective cell populations (CD103+ CD8+ T cells and Th17 cells), and promotes proliferation and activation of Th2 cells that can enhance RSV disease.

AB - We recently demonstrated that the respiratory syncytial virus (RSV) NS1 protein, an antagonist of host type I interferon (IFN-I) production and signaling, has a suppressive effect on the maturation of human dendritic cells (DC) that was only partly dependent on released IFN-I. Here we investigated whether NS1 affects the ability of DC to activate CD8+ and CD4+ T cells. Human DC were infected with RSV deletion mutants lacking the NS1 and/or NS2 genes and assayed for the ability to activate autologous T cells in vitro, which were analyzed by multi-color flow cytometry. Deletion of the NS1, but not NS2, protein resulted in three major effects: (i) an increased activation and proliferation of CD8+ T cells that express CD103, a tissue homing integrin that directs CD8+ T cells to mucosal epithelial cells of the respiratory tract and triggers cytolytic activity; (ii) an increased activation and proliferation of Th17 cells, which have recently been shown to have anti-viral effects and also indirectly attract neutrophils; and (iii) decreased activation of IL-4-producing CD4+ T cells - which are associated with enhanced RSV disease - and reduced proliferation of total CD4+ T cells. Except for total CD4+ T cell proliferation, none of the T cell effects appeared to be due to increased IFN-I signaling. In the infected DC, deletion of the NS1 and NS2 genes strongly up-regulated the expression of cytokines and other molecules involved in DC maturation. This was partly IFN-I-independent, and thus might account for the T cell effects. Taken together, these data demonstrate that the NS1 protein suppresses proliferation and activation of two of the protective cell populations (CD103+ CD8+ T cells and Th17 cells), and promotes proliferation and activation of Th2 cells that can enhance RSV disease.

UR - http://www.scopus.com/inward/record.url?scp=79955758958&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79955758958&partnerID=8YFLogxK

U2 - 10.1371/journal.ppat.1001336

DO - 10.1371/journal.ppat.1001336

M3 - Article

VL - 7

JO - PLoS Pathogens

JF - PLoS Pathogens

SN - 1553-7366

IS - 4

M1 - e1001336

ER -