The overall goal of our work is to identify mechanisms that regulate the activation and expansion of high avidity CD8+ T cells in response to virus infection in the lung. The difficulty in the development of protective vaccines for a number of clinically relevant respiratory viruses suggests that our understanding of the parameters that promote a protective immune response in the lung is incomplete. It has been shown previously that high avidity CD8+ T cells, which recognize low levels of antigenic peptide, are very potent immune cells since they recognize target cells at earlier times after infection and lyse infected cells more rapidly than low avidity cells. Thus the presence of high avidity cells is a key component of an optimal antiviral response. Our published data indicate that at early times after infection (d3) of the respiratory tract with the paramyxovirus simian virus 5 or the poxvirus vaccinia virus, the CD8+ T cell response is almost exclusively high avidity. However, at later times after infection (d5), low avidity cells are readily detected, comprising 50-60% of the total responding cells. Analysis of the CD8+ effector cells present in the lung identified a progressive loss in the ability of high avidity cells at this site to secrete IFN?, or lyse cells in response to stimulation. Loss of function selectively in high avidity cells is a novel form of immunosuppression.
In aim 1, we will determine the extent of the functional deficit in the high avidity cells and whether low avidity cells demonstrate defects consistent with the early stages of the induction of nonresponsiveness. Subsequent studies will investigate the mechanism responsible for the change in function. Finally we will test the hypothesis that changes over time in the inflammatory environment present in the lung, e.g. cytokines and nitric oxide, are responsible for the induction of nonresponsiveness in high avidity cells. The studies in aim 2 analyze the generation of the anti-viral CD8+ T cell response in the draining lymph node. We will test the hypothesis that the high avidity cells detected at early times postinfection can give rise to low avidity ceils present at later times. In addition we will test the hypothesis that the level of peptide presented or the antigen presenting cell present at various times post infection controls the selective presence of high avidity anti-viral CD8+ T cells at early times (d3) postinfection. Given the emerging threat of the aerosolized delivery of bioterrorism agents (including viruses) on the battlefield, it is of the utmost importance that we increase our understanding of the immune response elicited following respiratory infection and mechanisms by which these pathogens can suppress that response. Results from these studies should provide information that will promote development of new vaccines that will provide optimal protection against respiratory pathogens.
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