Among the most significant advances in immunology in the past decade has been the discovery of functionally different subsets of CD4+ T cells. Defined as TH1 or TH2 cells on the basis of the profiles of cytokines they secrete, these subsets have come to be recognized as the major cell types controlling a wide diversity of immune responses. Early investigations have provided evidence that TH1 immunity is essential for recovery from virus infection and evidence has been obtained that immunization with live RSV and influenza viruses lead to TH1 responses whereas inactivated viruses induce TH2 responses. In the present application, they propose to take advantage of this observation to compare molecular interactions involved in the response to live and inactivated virus. In particular, they will test the hypothesis that live virus activates NFkB activation which is sufficient to induce IL-12 release by dendritic cells, whereas IL-4 release in response to inactivated virus stimulates STAT6 which inhibits the action of NFkB. They plan to explore the mechanism whereby a TH2 response can be converted to a TH1 response using appropriate combinations of cytokines and anti-cytokines or Th1 stimuli such as CpG. They have evidence that demonstrates that they can induce TH1 memory to inactivated virus by the addition of cytokines and anti-cytokines. This is even more significant since animals immunized by this protocol clear subsequent virus infections in a facilitated manner. In this proposal, they will attempt to determine the cell types that are responsible for mediating this effect by the adoptive transfer of enriched T cell population and the depletion of CD8 cells. In addition, they propose to exploit our observation in an attempt to attain appropriate TH1 response and heterosubtypic immunity with inactivated HIV antigens. They will immunize with inactivated HIV and infect with transfectant influenza virus bearing CD4 and CD8 epitopes from HIV. They will also try to produce monoclonal antibodies to the IL-12B2 chain and to the gamma-interferon beta component. These may be extremely valuable reagents for analyzing or manipulating TH1 and TH2 immunity.
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