The applicant is committed to a career in academic medicine. He envisions a career in which basic science is applied to the problems in clinical medicine. The proposed research program is designed to enhance and strengthen the applicant's knowledge in immunology and his skill in basic science methodology which will be crucial to the development of a career as a physician scientist. The specific research proposal arises from the applicant's long-standing interest in T lymphocytes and their roles in allergic and infectious disease. The applicant has focused his research on the immune responses to Respiratory Syncytial Virus (RSV) because of its importance as human pathogen as well as its association with chronic airway diseases such as asthma. The applicant has established a murine model of RSV infection. An interesting finding which has been recently published is that mice sensitized to RSV-attachment glycoprotein develop a strong T cell response with high levels of IL-4 and IL-5 production which predisposes these animals to the development of lung eosinophilia. The lung pathology of these mice resembles the pathology observed in human cases that developed severe RSV pneumonia after receiving the formalin inactivated RSV vaccine. This murine model provides a unique opportunity to study the mechanisms of CD4+ T lymphocyte differentiation and the roles of T lymphocytes in this important viral infection. Recent studies by the applicant suggest that CD8+ T lymphocytes may play an important role in the regulation of CD4+ T cell differentiation. Induction of a strong CD8+ T cell response in mice sensitized to RSV- attachment glycoprotein suppresses the production of IL-4 and IL-5 as well as the development of lung eosinophilia. The focus of this proposal is to investigate the mechanisms by which CD8+ T cells exert their regulatory functions on the differentiation of CD4+ T cells. Using both in vitro and in vivo model, the impact of the activation of RSV-specific CD8+ T cells on the differentiation of CD4+ T cells at various stages of CD4+ T cell maturation will be examined. This work will provide insight into the process of CD4+ T cell differentiation and will have significance to the design of an effective vaccine against this important virus.
