Virus Clearance and Immunopathology by CD8(+) T Cells During Infection with Respiratory Syncytial Virus Are Mediated by IFN-gamma

CD8(+) T cells (CTL) are important effector cells for virus control and immunopathology after primary infection with respiratory syncytial virus (RSV). To investigate the effector mechanisms involved, we set up an adoptive transfer model, in which effector CTL specific for p82-90 of RSV M2 were generated in vivo, followed by short-term restimulation in vitro and transfusion into infected recipients. A total of 4 x 10(4) donor-derived p82-specific CTL homing to the lung within 4 days after transfusion were sufficient to completely eliminate a virusinoculum of 1.5 x 10(6) pfu. This was accompanied by significant lung pathology. Surprisingly, virus control and immunopathology proceeded unimpaired when donor cells lacking perforin, CD95 ligand or TNF were transfused. By contrast, treatment of recipient mice with a neutralizing antibody against IFN-gamma or transfusion of IFN-gamma-deficient effector CTL largely abolished virus control and significantly reduced CD8(+) T cell-mediated pathology. In IFN-gamma-deficient mice, high-dose primary infection experiments revealed attenuated immunopathology, but only slightly delayedvirus clearance, suggesting that other cells and molecules can partly substitute for the effects of CTL-derived IFN-gamma on virus clearance. These experiments identify IFN-gamma as a key molecule in RSV-induced immunopathology and in CD8(+) T cell-mediated control of RSV infection.