CD4 T cell Immunity to Influenza

甲型流感（fluA）优先在呼吸道复制，是一种有用的原型

Influenza A (fluA) preferentially replicates in the respiratory tract, and is a useful prototype for understanding human immune defense mechanisms that limit respiratory infection and transmission. FluA infection causes annual substantial morbidity and mortality worldwide for infants and the elderly, and is of potential concern as a agent of bioterrorism because of its ability to readily undergo genetic reassortment and be generated by recombinant DNA technology. The current approved FluA vaccines are the trivalent inactivated vaccine (TIV) and Flumist, a trivalent live-attenuated vaccine given intranasally. However, little is known concerning the cellular immune responses to vaccine compared to natural infection, including at the extremes of age. CD4 T cells are key component of the fluA immune response by providing CD 154-mediated help to B cells for the production of neutralizing antibodies to hemagglutinin (HA), which protect against infection and disease. CD4 T cells also provide help to CD8 T cells and produce interferon-gamma (IFN-],) and tumor necrosis-factor-alpha (TNF-c_), which have direct anti-viral activity. The main goal of this project is to use contemporary single-cell based assays, including those developed by Technical Projects A-D, to determine the fluAspecific CD4 T cell response. FluA-specific and HA-specific CD4 T cell responses will be analyzed for expression of IFN-% TNF-c_, and CD154, and the overall frequency of antigen-reactive CD4 T cells based on TCR specificity. The focus will be on the response to natural fluA infection in children, and to parenteral or mucosal vaccination in both children and adults. A second focus is to define a G proteinlinked chemotactic receptor phenotype of CD4 T cells that preferentially home to the lung, and the frequency of these cells in the blood following fluA infection or fluA vaccination. These studies will provide substantial new insights into human CD4 T cell responses to fluA infection and vaccination, including at the extremes of age, and their relationship to other lymphocyte effector mechanisms (Projects 2-4). They may also indicate strategies to augment pulmonary host defense mechanisms.