Abstract
TSLP is an IL-7 like cytokine that is primarily produced by epithelial cells at mucosal surfaces. It has been widely studied in Th2-driven inflammatory disorders such as atopic dermatitis and asthma. Although both viral nucleic acid analogues and pro-inflammatory cytokines associated with active viral infections are potent stimulators of TSLP expression in vitro, it's role in antiviral immunity is unknown. To elucidate the role of TSLP in viral infections, we investigated the immune response against influenza A in mice deficient in TSLPR. We found that TSLPR-deficient mice exhibited impaired clearance of the virus at late time points post infection, indicative of a defect in the adaptive immune response. Although priming in the lymph node was unaffected, the virus-specific CD8+ T cell response in the lung was compromised in the absence of TSLPR. This defect was characterized by the reduced frequency of virus-specific CD8 T cells as well as reduced effector functions such as granzyme B expression and interferon-γ production. Using mixed bone marrow chimeras and adoptive transfer studies, our data suggests that TSLP affects influenza-specific responses by modulating the function of recruited inflammatory dendritic cells (DCs). Pulmonary DCs isolated from infected lungs of TSLPR deficient mice were defective in inducing proliferation of antigen specific naïve T cells in vitro. Furthermore in the absence of TSLPR the production and trans presentation of IL-15 by CD11b+ inflammatory DC was impaired. We propose that TSLP regulates activation of antigen specific cytotoxic T cells at the site of infection by modulation of DC function and suggest a crucial link between TSLP and IL-15 production during infection.
- © 2011 ERS