Although several risk factors for asthma have been defined the etiology for childhood asthma remains poorly understood. In particular, the role of viral respiratory tract infection in the development of this disease remains controversial. Infection with respiratory viruses, such as Respiratory Syncytial Virus (RSV), has been reported to predispose children to the subsequent development of asthma. In contrast, some epidemiologic studies have suggested that viral infection of the respiratory tract may have a protective effect against the development of this disease. In a major of asthmatic patients, particularly children, sensitizing and exposure to allergens is a major risk factor in the development of asthma. Recently, a critical a critical role of CD4+ T cells in the development of allergic responses has become clear. In particular, CD4+ T cells which are capable of producing IL-4 and IL-5 (Th2 T cells) are required for establishing an allergic response. Recent evidence from human and animal studies have also demonstrated the importance of this subset of CD4+ T cells in viral infections. In a murine model of RSV infection, sensitization to the RSV-G (attachment) glycoprotein results in a strong Th2 response and predisposes the animals to the development of allergic lung inflammation. Insights into the factors regulating the differentiation and activation of this subset of subset of CD4+ T cells is therefore extremely important to the understanding of the role of viral infections in the development of asthma. Recently, a study has demonstrated that the strong induction of a Th2 response by RSV-G glycoprotein is linked to the lack of memory of CD8+ T cell response specific to this antigen. This suggests that virus-specific CD8+ T cell may play an important role in the regulation of Th2 responses. The studies outlined in this proposal are designed to examine the role of virus-specific CD8+ T cells on the differentiation of CD4+ T cells of Th2 phenotype. Specifically, studies will focus on 1) the role of CD8+ T cells in regulating CD4+ T cell differentiation and the impact of this regulation on the kinetic of CD4+ T cell differentiation, 2) the molecular mechanisms employed by CD8+ T cells in this regulation, and 3) the impact of this regulation on allergic inflammation in an animal model of RSV infection. Studies will be carried out to examine the role of respiratory viral infection on allergen-specific T cell responses in human. Theses studies will lead to new insights into the role of virus-specific CD8+ T cells in the development of allergic lung diseases.
| Lajoie, Stephane; Lewkowich, Ian P; Suzuki, Yusuke et al. (2010) Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nat Immunol 11:928-35 |
