TRANSCRIPTIONAL REGULATION OF T-CELL RECEPTOR GENES

The diverse lineages of the mammalian hematopoietic system including both B and T lymphocytes are derived from a single mesodermal progenitor, the pluripotent bone marrow stem cell. The coordinate transcriptional regulation of sets of lineage-specific genes is one of the important molecular mechanisms underlying hematopoietic lineage determination and differentiation. The immunoglobulin and T cell receptor (TCR) genes have been used as model systems to study lineage-specific transcriptional regulation during lymphoid development. This review summarizes our current understanding of the regulation of TCR gene expression during thymocyte ontogeny. Expression of each of the TCR genes is controlled by T cell-specific transcriptional enhancers that bind partially overlapping sets of ubiquitous and lymphoid-specific transcription factors. These include members of both the ATF/CREB family of basic-leucine zipper proteins and the Ets protooncogene family, as well as the T cell-specific zinc finger transcription factor, GATA-3, and the T cell-specific high mobility group proteins TCF-1 and TCF-1alpha/LEF-1. The identification of binding sites for these same transcription factors in a number of additional T cell-specific genes suggests that they may play important roles in the coordinate regulation of gene expression that specifies the development of the T cell lineages. Recent studies of the TCR alpha and gamma genes have suggested that negative regulatory elements or transcriptional silencers may also play an important role in controlling the lineage-specific expression of these genes. On going studies are designed to clarify the role of each of the TCR enhancer binding proteins in regulating T cell development in vivo, to more precisely define the interactions between the TCR enhancer binding proteins, and to elucidate the molecular mechanisms underlying transcriptional silencer activity.