Herpes simplex virus (HSV) is a common pathogen in humans. Corneal inflammation and scarring is a potentially blinding complication of HSV-l ocular infections in patients who appear to be immunologically normal. When a patient becomes immunologically compromised, an HSV-l infection that is normally localized can disseminate to a variety of organs including the brain, where it can cause a lethal encephalitis. Due to the ability of the virus to be transmitted across tight cellular junctions with minimal exposure to the extracellular space, antibodies tend to be ineffective at halting the spread of the virus. Cytotologic T lymphocytes (CTL) are capable of recognizing processed vital proteins early in the infectious process prior to production of new virus particles. For this reason, cytotoxic function is considered to be an important component of the host defense against HSV-l infections. However, surprisingly little is known about the mechanisms that control CTL function within the microenvironment of the infected tissue. Recent evidence suggests that individual CTL clones may vary in their requirements for accessory molecule expression on target cells. Moreover, the array of accessory molecules that is expressed may vary on target cells derived from different tissues. The regulation of CTL activity in HSV-l infected tissue is further complicated by the fact that the virus itself may inhibit presentation of its own antigens to T cells by blocking the transmission of MHC class l molecules to the cell surface. For these reasons, we believe that the potential for CTL protection can only be evaluated when their activity is measured under conditions that mimic the microenvironment of the infected tissue of interest. The proposed studies will investigate the interaction and cross-regulation among CTL, tissue cells, and HSV-l in the mieroenvironment of infected eyelids and corneas. We will employ three approaches to define these interactions: (l) define phenotypic changes that occur in the CTL precursors as they differentiate into active cytotoxic cells, and where in their progress from lymph nodes to the infected tissue differentiation occurs; (2) evaluate the ability of cells derived from cornea and eyelid tissues to serve as targets for CTL, the accessory molecules that contribute to the interaction, and how the interaction is regulated by HSV-l infection and cytokines that are present in the infected tissues; (3) determine if cells from infected tissue can influence the process of CTL differentiation. To our knowledge these studies represent the first attempt to characterize HSV-specific CTL function in a system that recognizes the regulatory influences that may be uniquely expressed in a specific HSV-l-infected tissue. We believe that these investigations are justified by the enormous potential of CTL for controlling the dissemination of the virus with minimal immunopathology in these sensitive tissues.
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