THYMUS LEUKEMIA GENES AND ANTIGENS

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A study of the thymus-leukemia (TL) antigens' amino acid sequence lends credence to the hypothesis that TL proteins may possess an antigen binding cleft similar to that found on the paradigmatic HLA-A2 class I glycoprotein. Like HLA-A2, but in a far more restricted manner, the TL molecules may be capable of binding and presenting antigen. In this context, recent reports have implicated TL as the antigen presenting ligand for gamma/delta T cell receptor (TcR) molecules. Thus, the long-term objectives of this proposal are to understand both the biological function of the TL family of class I genes and proteins as well as the molecular mechanisms which regulate the genes' tissue-specific expression. Specifically, transgenic mice will be produced and used to study the pattern of expression of TL driven by the H-2Kb promoter. Initial experiments have demonstrated that the gene is expressed in such mice similar to endogenous H-2 class I proteins. Antibodies against TcR, CD4, and CD8 molecules will first be used to stain transgenic immune cells in order to determine whether ectopic expression of TL results in the perturbation of T cell differentiative pathways. Immunologically, TL will be assessed for its ability to serve as a transplantation antigen and a CTL restriction element using virus models. Positive results will allow for the cloning of the effector T cells and an examination of their TcR molecules. Such results can yield an indication as to the ligand with which TL interacts in vivo as well as TL's possible functional role. These experiments can also form the basis for future structure-function studies. Experiments involving the analysis of novel mAb antibodies putatively reacting with TL peptides derived from unspliced TL transcripts as well as the identification of TL promoter elements involved in splicing and tissue-specific TL expression will be continued.