Effector T lymphocytes recognize antigens in association with a product of the major histocompatibility complex (MHC) through the T-cell receptor for antigen (TCR), a heterodimer composed of disulfide-linked alpha and beta chains. The appropriate pool of alpha/beta TCR-bearing cells is generated in the thymus upon positive and negative selection, a process called thymic education which eliminates TCRs with a high affinity for self MHC alone while expanding T cells bearing TCRs with affinity for self in association with foreign antigens. In addition to the alpha/beta TCR, a second TCR, termed gamma/delta, has been described on the surface of a small subset of immature T cells and thymocytes. This project aims to delineate the unknown function and the ligand(s) of the gamma/delta TCR. Because of its expression in immature T cells and thymocytes, it has been proposed that the gamma/delta TCR may play a role during the early events of thymic T cell development, including thymic education. In order to dissect this project at the molecular level, we have first sought to define the complexity of the variable (V), diversity (D), and joining (J) element usage for the newly- described human delta TCR gene, because these elements combine to form the ligand-binding part of the receptor. We find that principally three V genes, 2 D genes, and only one J gene are used in the human contributing to all of the complexity of the gene. Genomic clones are being derived for each of these V genes, as well as for the D and J regions, which will be used to study the ontogeny of the gene's expression in human thymus. In addition, it has recently been possible to develop antigen-specific murine gamma/delta cell lines directed alternatively against class I MHC or class II MHC determinants. Genomic libraries generated from the DNA of these lines are used to isolate their antigen-specific gamma/delta genes as a first step toward developing transgenic mice bearing these genes. These transgenic mice will be an important in vivo model to study the function of the gamma/delta TCR.
