CD8⁺ T cells control Th2-driven pathology during pulmonary respiratory syncytial virus infection

BALB/c mice vaccinated with vaccinia virus expressing the major surface glycoprotein G of respiratory syncytial virus (RSV) develop lung eosinophilia during RSV challenge. The G protein is remarkable in that it induces CD4⁺, but no CD8⁺ T cells in this mouse strain. Studies using passive T cell transfers show that co-injection of CD8⁺ T cells greatly reduces the Th2-driven lung eosinophilia caused by G-specific CD4⁺ T cells. By contrast, vaccination with the fusion protein (F) induces both CD8⁺ and CD4⁺ T cells, but not lung eosinophilia during RSV infection. These observations suggest that CD8⁺ T cells play a crucial role in preventing Th2-driven pathology. We therefore depleted mice with anti-CD8 antibodies in vivo. This treatment allowed lung eosinophilia to develop in F-primed mice. Depletion of interferon (IFN)-γ had a similar effect, suggesting that secretion of this cytokine is the mechanism by which CD8⁺ T cells exert their effect. To test whether similar effects occurred in other strains of mice, RSV-infected C57BL/6 mice (which do not develop eosinophilia after sensitization to G) were treated with anti-IFN-γ. Again, these mice developed eosinophilia. In this strain, genetic deletion of CD8-α, β2-microglobulin or genes coding for the transporter associated with antigen presentation (which in each case eliminates CD8⁺ T cells) caused lung eosinophilia during RSV infection. These studies show the critical roles that CD8⁺ T cells and IFN-γ production play in regulating Th2-driven eosinophilia and provide a unifying explanation for previous studies of lung eosinophilia. We propose that vaccines designed to enhance CD8⁺ T cell recognition might avoid disease caused by CD4⁺ Th2 cells.