IL-12-Activated NK Cells Reduce Lung Eosinophilia to the Attachment Protein of Respiratory Syncytial Virus But Do Not Enhance the Severity of Illness in CD8 T Cell-Immunodeficient Conditions

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Abstract
Bronchiolitis caused by respiratory syncytial virus (RSV) infection is a major cause of hospitalization in children under 1 year of age. RSV causes common colds in older children and adults, but can cause serious disease in immunodeficient patients and the elderly. Development of effective vaccines and treatments for RSV infection is therefore a priority. Because bronchiolitis and vaccine-augmented disease are thought to be caused by exuberant T cell activation, attention has focused on the use of immunomodulators that affect T cell responses. In mice, IL-12 treatment down-regulates type 2 cytokine responses to the attachment protein G of RSV, reducing lung eosinophilia but further enhancing illness. We now show that CD8+ T cells are responsible for enhanced weight loss, whereas IL-12-activated NK cells express high levels of IFN-γ and inhibit lung eosinophilia without causing illness. Moreover, unlike immunocompetent mice, virus is detected in the mediastinal lymph nodes after elimination of both CD8+ T cells and NK cells. These studies show that innate immune responses to viral infections direct the pattern of subsequent specific immunity and are critical to the development of nonpathogenic antiviral effects. We speculate that IL-12 treatment might be beneficial and safe in T cell-deficient patients with RSV pneumonitis.