Accessibility control of variable region gene assembly during T-cell development

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T-cell development is a complex and ordered process that is regulated in part by the progressive assembly and expression of antigen receptor genes. T cells can be divided into two lineages based on expression of either an αβ or γδ T-cell antigen receptor (TCR). The genes that encode the TCR β and γ chains lie in distinct loci, whereas the genes that encode the TCR α and δ chains lie in a single locus (TCR α/δ locus). Assembly of TCR variable region genes is mediated by a site-specific recombination process that is common among all lymphocytes. Despite the common nature of this process, recombination of TCR genes is tightly regulated within the context of the developing T cell. TCR β, γ and δ variable region genes are assembled prior to TCR α variable region genes. Furthermore, assembly of TCR β variable region genes is regulated within the context of allelic exclusion. The regulation of rearrangement and expression of genes within the TCR α/δ locus presents a complicated problem. TCR α and δ variable region genes are assembled at different stages of T-cell development, and fully assembled TCR α and δ variable region genes must be expressed in distinct lineages of T cells, αβ and γδ, respectively. We have developed several experimental approaches to assess the role of cis-acting elements in regulating recombination and expression of TCR genes. Here we describe these approaches and discuss our analyses of the regulation of accessibility of the TCR β and TCR α/δ loci during T-cell development.

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