Abstract
IFNs protect from virus infection by inducing an antiviral state and by modulating the immune response. Using mice deficient in multiple aspects of IFN signaling, we found that type I and type II IFN play distinct although complementing roles in the resolution of influenza viral disease. Both types of IFN influenced the profile of cytokines produced by T lymphocytes, with a significant bias toward Th2 differentiation occurring in the absence of responsiveness to either IFN. However, although a Th1 bias produced through inhibition of Th2 differentiation by IFN-gamma was not required to resolve infection, loss of type I IFN responsiveness led to exacerbated disease pathology characterized by granulocytic pulmonary inflammatory infiltrates. Responsiveness to type I IFN did not influence the generation of virus-specific cytotoxic lymphocytes or the rate of viral clearance, but induction of IL-10 and IL-15 in infected lungs through a type I IFN-dependent pathway correlated with a protective response to virus. Combined loss of both IFN pathways led to a severely polarized proinflammatory immune response and exacerbated disease. These results reveal an unexpected role for type I IFN in coordinating the host response to viral infection and controlling inflammation in the absence of a direct effect on virus replication.
Highlights
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To characterize the cellular immune response to influenza virus, CTL activity was measured with the use of splenocytes derived from C57BL6 mice immunized in vivo by i.p. injection of a sublethal dose of PR8 virus (Fig. 1)
Mice generated cytotoxic lymphocytes capable of killing target cells pulsed with the immunodominant influenza virus peptide presented by H-2Db [16]
Summary
The production of Stat1Ϫ/Ϫ mice on a CD1 background has been previously described [6]. Influenza A/PR/8/34 (H1N1) (PR8) was grown in the allantoic cavities of 10-day-old embryonated eggs (SPAFAS, Preston, CT) and titered by plaque formation on Madin-Darby canine kidney cells in the presence of trypsin or by hemagglutination (HA) assay. Virus production assays to determine tissue culture infectious dose (TCID) were performed on confluent monolayers of Madin-Darby canine kidney cells in 96-well plates infected with dilutions of viral suspensions. Animals with positive influenza virus-specific Ab titers and control animals that had been inoculated with PBS alone were rechallenged with 105 PFU WSN, and animals were monitored as described above. One lung from each animal was homogenized in 2 ml PBS, and the presence of influenza virus was quantified by virus production/HA assay. For measurement of cytokine transcripts from lymphocytes, splenocytes were cultured for 4 days with plate-bound anti-CD3 (2C11) plus antimouse CD28 (37.51) Abs and IL-2. Cells were subsequently fixed and permeabilized with Fix & Perm reagent (Caltag), followed by staining with antiIFN-␥-FITC and anti-IL-5-PE Abs (Caltag)
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