Influenza-induced expression of functional tumor necrosis factor-related apoptosis-inducing ligand on human peripheral blood mononuclear cells.
The immunologic response to influenza virus infection, like many other viruses, is characterized by robust production of proinflammatory cytokines, including type I and II interferon (IFN), which induce a number of antiviral effects and are essential for priming the innate and adaptive cellular components of the immune response. Here, we demonstrate that influenza virus infection induces the expression of functional tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on human peripheral blood mononuclear cell (PBMC) populations. Consistent with previous studies examining TRAIL upregulation, increased TRAIL expression correlated with increased type I and II IFN levels in PBMC cultures. Interestingly, dilution of these cytokines resulted in decreased expression of TRAIL. TRAIL upregulation was not dependent on active viral infection, and TRAIL was observed on NS-1-negative cells. Furthermore, influenza virus infection of lung adenocarcinoma cells (A549) resulted in increased sensitization to TRAIL-induced apoptosis compared with uninfected A549. Infected PBMC expressing TRAIL preferentially killed infected A549, but did not affect uninfected cells, and the addition of soluble TRAIL-R2:Fc blocked the lysis of infected cells, demonstrating TRAIL-dependent killing of infected cells. Collectively, these data demonstrate that TRAIL expression is induced on primary human innate and adaptive immune cells in response to cytokines produced during influenza infection and that TRAIL sensitivity is increased in influenza virus-infected cells. These data also suggest that TRAIL is a primary mechanism used by influenza-stimulated human PBMC to kill influenza-infected target cells and reinforce the importance of cytokines produced in response to TLR agonists in enhancing cellular immune effector functions.
Brincks
Erik L
EL
Department of Urology, University of Iowa, Iowa City, IA, USA.
Kucaba
Tamara A
TA
Legge
Kevin L
KL
Griffith
Thomas S
TS
D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D005786:Gene Expression Regulation; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008168:Lung / Q000166:cytology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*
D016898:Interferon-alpha; D053221:TNF-Related Apoptosis-Inducing Ligand; D007371:Interferon-gamma