Environmental factors, especially pathogenic microorganisms, have been implicated in the initiation or exacerbation of many destructive immunological processes. A successful cytotoxic T lymphocyte (CTL) response requires two consecutive signals. Signal 1 is the precise recognition by the T- cell receptor complex of antigen + MHC class I protein. Signal 2 is the delivery of """"""""help"""""""" occurring within a window of time subsequent to Signal 1. Because it depends on the delivery of antigen-nonspecific cytokines, Signal 2 is promiscuous in nature and thus a weak link in specific immunity. Conceptually, a wide range of microorganisms could provide help and thus promote the CTL response to completely unrelated antigens. The overall goal of the proposed work is to characterize the cellular mechanisms through which such organisms deliver help to CTL in vivo. The minor H antigen model system will be utilized because it is a uniquely sensitive experimental system for studying responses to weak transplantation antigens (referred to as Type I minor H antigens) in vivo that selectively stimulate the CD8+ T-cell subset, and thus, are strongly dependent upon help. This model serves as a realistic paradigm not only for allogeneic tissue transplantation, but also for tumor immunity and autoimmunity. The central hypothesis is that apparently unrelated immunological stimuli can deliver Signal 2 to the CTL response against a Type I minor H antigen. The application proposes to establish how help is delivered in vivo in a comparatively well-controlled experimental situation. The immunological consequences of Type I antigen presentation will be examined on different cell types. The studies will address whether help is provided to CTL by B-cells or during Th-B-cell collaboration. These studies should elucidate the cellular pathways by which Signal 2 can be delivered in vivo to CTL and provide a solid foundation for experiments that follow. P. acnes is a ubiquitous organism that colonizes the skin and displays features of a potent immunological adjuvant. Coincidentally, it has been found to promote help for the CTL response to minor H antigens. Next, the studies will characterize the effects of systemic delivery of help by P. acnes, examining whether it leads to tissue rejection or tolerance. The application will test the hypothesis that P. acnes induces a state of promiscuous help, which can pass the usual requirement for linked recognition between Th + CTL. These studies will provide a detailed examination into how a microbial adjuvant potentiates endogenous immunity. Finally, the application will establish three novel experimental paradigms that focus on the interaction of environment and the CTL and allograft response to a minor H antigen. The first examines differences in mouse colony environments. The second examines local administration P. acnes.The third examines the effects of bacterially- induced periodontal disease. These studies should provide a unique assessment of our hypothesis and create new experimental avenues to assess the role of environmental microbes on the host immune system.
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