Alpha and lambda interferon together mediate suppression of CD4 T cells induced by respiratory syncytial virus.
The mechanism by which respiratory syncytial virus (RSV) suppresses T-cell proliferation to itself and other antigens is poorly understood. We used monocyte-derived dendritic cells (MDDC) and CD4 T cells and measured [(3)H]thymidine incorporation to determine the factors responsible for RSV-induced T-cell suppression. These two cell types were sufficient for RSV-induced suppression of T-cell proliferation in response to cytomegalovirus or Staphylococcus enterotoxin B. Suppressive activity was transferable with supernatants from RSV-infected MDDC and was not due to transfer of live virus or RSV F (fusion) protein. Supernatants from RSV-infected MDDC, but not MDDC exposed to UV-killed RSV or mock conditions, contained alpha interferon (IFN-alpha; median, 43 pg/ml) and IFN-lambda (approximately 1 to 20 ng/ml). Neutralization of IFN-alpha with monoclonal antibody (MAb) against one of its receptor chains, IFNAR2, or of IFN-lambda with MAb against either of its receptor chains, IFN-lambdaR1 (interleukin 28R [IL-28R]) or IL-10R2, had a modest effect. In contrast, blocking the two receptors together markedly reduced or completely blocked the RSV-induced suppression of CD4 T-cell proliferation. Defining the mechanism of RSV-induced suppression may guide vaccine design and provide insight into previously uncharacterized human T-cell responses and activities of interferons.
Chi
Bo
B
Center for Biologics Evaluation and Research, Bethesda, MD 20892, USA.
Dickensheets
Harold L
HL
Spann
Kirsten M
KM
Alston
Marc A
MA
Luongo
Cindy
C
Dumoutier
Laure
L
Huang
Jiaying
J
Renauld
Jean-Christophe
JC
Kotenko
Sergei V
SV
Roederer
Mario
M
Beeler
Judy A
JA
Donnelly
Raymond P
RP
Collins
Peter L
PL
Rabin
Ronald L
RL
D000328:Adult; D000942:Antigens, Bacterial / Q000494:pharmacology; D000956:Antigens, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002460:Cell Line; D049109:Cell Proliferation; D002474:Cell-Free System / Q000276:immunology; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D003587:Cytomegalovirus / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004357:Drug Synergism; D004768:Enterotoxins / Q000494:pharmacology; D006801:Humans; D007165:Immunosuppression Therapy; D016898:Interferon-alpha / Q000494:pharmacology / Q000502:physiology*; D007372:Interferons; D007378:Interleukins / Q000494:pharmacology / Q000502:physiology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D018113:Respiratory Syncytial Virus, Human / Q000276:immunology*; D000095022:Interferon Lambda
D000942:Antigens, Bacterial; D000956:Antigens, Viral; D000998:Antiviral Agents; D016207:Cytokines; D004768:Enterotoxins; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C031818:enterotoxin B, staphylococcal