The cytotoxic T cell (CTL) specifically recognizes and kills by direct lysis target cells which are diseased or foreign. CTL recognition is advantageous to the host when the target cells are malignantly transformed or virally infected and nonadvantageous to the host when the target cells are from transplanted or self tissue. The clinical benefits of manipulating the CTL response are clear. This will require a thorough understanding of CTL activation and recognition. The generation of a CTL response involves the interaction of several cell types; pre CTL, T helper cells (TH) and antigen presenting cells (APC).
The aim of this project is to more precisely define the interactions involved in generating the CTL response to major histocompatibility complex (MHC) antigens. MHC antigens are used because purified antigen can be inserted in liposomes and used to stimulate a T cell response. Use of this antigen will allow biochemical and genetic manipulation of the antigen to assess the specificity requirements for T cell recognition. The role of other T cell surface molecules will be examined to determine their functional relevance to T cell activation. The cellular and biochemical pathways for their action will be investigated. Antibodies to T cell surface markers will be used to determine the role of accessory molecules in T cell activation. Expression of human T cell surface molecules via retroviral infection of murine xenogeneic T cell hybridomas will be used to assess the contribution of accessory molecules in T cell activation. Mutant constructs of these gene products will allow an examination of their functional domains. Defining the requirements for the generation of T cell responses will clarify the pathway for clinical intervention in the T cell mediated responses. A more complete understanding of the T cell accessory molecules, CD4 and CD8 will aid in the understanding of T cell activation and may suggest clinical modalities to address AIDS as CD4 is the cellular receptor for HIV-3.
