The TCRalpha locus control region specifies thymic, but not peripheral, patterns of TCRalpha gene expression

The molecular mechanisms ensuring the ordered expression of TCR genes are critical for proper T cell development. The mouse TCR alpha-chain gene locus contains a cis-acting locus control region (LCR) that has been shown to direct integration site-independent, lymphoid organ-specific expression of transgenes in vivo. However, the fine cell type specificity and developmental timing of TCRalpha LCR activity are both still unknown. To address these questions, we established a transgenic reporter model of TCRalpha LCR function that allows for analysis of LCR activity in individual cells by the use of flow cytometry. In this study we report the activation of TCRalpha LCR activity at the CD4-CD8-CD25-CD44- stage of thymocyte development that coincides with the onset of endogenous TCRalpha gene rearrangement and expression. Surprisingly, TCRalpha LCR activity appears to decrease in peripheral T cells where TCRalpha mRNA is normally up-regulated. Furthermore, LCR-linked transgene activity is evident in gammadelta T cells and B cells. These data show that the LCR has all the elements required to reliably reproduce a developmentally correct TCRalpha-like expression pattern during thymic development and unexpectedly indicate that separate gene regulatory mechanisms are acting on the TCRalpha gene in peripheral T cells to ensure its high level and fine cell type-specific expression.