Pulmonary Eosinophilia Is Attenuated by Early Responding CD8+Memory T Cells in a Murine Model of RSV Vaccine-Enhanced Disease

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Abstract
Vaccination with formalin-inactivated respiratory syncytial virus (RSV) vaccine results in enhanced respiratory tract inflammation and injury following subsequent RSV infection. RSV vaccine-enhanced disease can also be produced in mice by prior vaccination with a vaccinia virus vector containing the RSV G protein, followed by intranasal infectious RSV challenge, a process characterized by induction of a potent memory CD4+ T-cell response to challenge infection with some features characteristic of Th-2 CD4+ T-cell responses, including increased eosinophil accumulation in pulmonary inflammatory infiltrates. The adaptive immune response to the RSV G protein in immunized BALB/c mice is characterized by a weak or absent primary and secondary recall CD8+ T-cell response. These and related results have led to the hypothesis that the failure of the infected animals to mount an effective CD8+ memory T-cell (CD8+ Tm) response in this model could account for the pulmonary eosinophilia associated with the development of enhanced disease, and that CD8+ T cells may control the development of eosinophilia. In this study, we investigated how and when the generation of a CD8+ Tm response to RSV infection might affect the development of pulmonary eosinophilia in this model of vaccine-enhanced disease. By defining the CD8+ T-cell response kinetics and monitoring lung parenchymal eosinophil accumulation, we show that the establishment of an RSV-specific CD8+ Tm response in the infected lungs early after challenge infection (i.e., within the first 3 d of RSV infection) is necessary and sufficient to control pulmonary eosinophilia development. Additionally, our work suggests that the mechanism by which CD8+ T cells regulate this process is not by modulating the differentiation or development of the CD4+ Tm response. Rather, we demonstrate that IL-10 produced by early responding CD8+ Tm cells may regulate the pulmonary eosinophilia development observed in RSV vaccine-enhanced disease.