The immune system plays the major role in the host response to infection and in the clearance of infectious microorganisms from the body. Both the cell-mediated and humoral arms of the immune system function in th response to infection. It is also evident that dysfunction or disregulation of one or both arms of the immune system can lead to disorders of immune function, including asthma, allergies and autoimmune injury. Over the past 5-7 years it has become clear that CD4+ T lymphocytes can be divided into subsets, i.e., CD4+ Th1, CD4+ Th2, based on their cytokine release in response to antigen. Cells of the CD4+ Th2 subset have been implicated in the formation of specific IgE antibodies and in allergic responses through the action of specific cytokines produced by this T cell subset. Viruses of the paramyxovirus group are important human pathogens. Among this virus group Respiratory Syncytial Virus (RSV) is a major cause of morbidity among infants and young children and can result in moderate to severe pulmonary disease. Recently several lines of evidence suggest that the immune response to RSV may itself enhance pulmonary injury and that RSV may selectively activate CD4+ T lymphocytes of the Th2 subset. The studies outlined in this proposal are designed to investigate the role of specific RSV gene products in the induction of RSV virus specific CD4+ and CD8+ T lymphocytes. Initial studies will focus on the induction of CD8+ and CD4+ T lymphocytes in response to specific RSV virion proteins and will examine the role of RSV-G glycoprotein as a selective inducer of CD4+ Th2 T lymphocyte responses in experimental animals. Related studies will assess the ability of RSV-G specific T cell clones of the Th1 and Th2 phenotype to induce virus clearance and pulmonary injury. Another series of experiments will focus on the proliferative response and cytokine profile of peripheral T lymphocytes obtained from RSV immune human donors in response to RSV virus in specific RSV proteins. These studies will investigate if there is preferential activation of CD4+ Th2 cells in response to RSV or specific RSV proteins. Finally, studies will be undertaken to evaluate the mechanism by which a specific RSV viral protein can activate CD4+ T cells to differentiate into cells of the CD4+ Th2 pathway. The proposed studies should provide information on the role of RSV and specific viral proteins in pulmonary injury and predisposing to allergic pulmonary disease. In addition these studies should provide new insights into the mechanism(s) by which environmental antigens like RSV proteins may drive T lymphocyte activation and differentiation into the Th2 phenotype.
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