The cytolytic T lymphocyte (CTL) specifically recognizes and kills by direct lysis cells (targets) which are diseased or foreign. CTL recognition is advantageous to the host when the target is a virally infected cell or a malignantly transformed cell, and nonadvantageous to the host when the target is transplanted tissue resulting in allograft rejection or when the target is normal tissue resulting in autoimmune disease. The clinical benefits of manipulating the CTL response are clear; however, safe manipulation will almost certainly require an understanding of CTL-target cell recognition at the molecular level. It has been established that CTL recognize virus or tumor antigens only in the context of self major histocompatability (MHC) complex proteins on the target cell surface while allograft rejection appears to require only MHC proteins different from self on the target cell. However, other than the qualitative requirement of foreign antigen and MHC proteins, target cell components necessary for optimal CTL recognition have not been defined. The overall aim of this project is to more precisely define the physical and molecular properties of target cells which are needed for optimal recognition by CTL. The specific target cell properties to be examined are: requirement for target membrane cytoskeleton and related components, target size and surface density of H-2 required for optimal CTL recognition, requirement for non H-2 target cell surface components, and minimal target properties required for direct alloantigen stimulation of pre-CTL in the absence of antigen presenting cells. Target properties will be defined employing the following approaches: liposomes containing purified alloantigen, H-2Kk (intact or modified), will be used to deliver the antigen signal for generation of a CTL response; intact cells, syngeneic or H-2 negative, will be fused with liposomes bearing H-2Kk (intact or modified) and used to generate a CTL response, or serve as targets for CTL mediated lysis; intact cells selected for cell surface properties or expression of genetically manipulated H-2 will be used as targets for CTL recognition; and cell surface behavior of H-2, such as lateral mobility, will be examined and related to CTL recognition. Defining the molecular properties of a target allowing maximal CTL recognition should facilitate understanding the molecular mechanism of CTL recognition, as well as furnish a blueprint for constructing an artificial vesicle that will be directly recognized by CTL.
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