Insights into the Transcriptional Regulation of the Unrearranged and Rearranged Tcra and Tcrd Genes

Cristina Hernandez Munain

doi:10.4172/2155-9899.1000415

Abstract

The combined T-cell receptor α and δ locus, Tcra/Tcrd, encodes the TCRα and TCRδ chains of the αβ or γδ T-cell receptors (TCRαβ and TCRγδ), respectively, which define the two distinct T-cell lineages, αβ and γδ T lymphocytes. Like other antigen receptor loci, this locus must recombine its variable (V), diversity (D), and joining (J) gene segments to generate a diverse range of TCR that allow vertebrates to respond to an unlimited number of antigens. The Tcra/Tcrd germline transcription and subsequent V(D)J gene segment rearrangements are strictly regulated by two distant transcriptional enhancers, Eα and Eδ, respectively, during thymocyte development. Once the Tcra locus is productively rearranged, it is assumed Eα remains active for the transcription of the rearranged locus and the expression of the functional TCRα chain in αβ T lymphocytes. However, our recent experiments have shown Eα is significantly inhibited during the final stage of thymocyte development, concomitantly with the expression of the rearranged Tcra locus, and remains inhibited in αβ T lymphocytes. These results imply the existence of an Eα-independent mechanism to activate transcription of the rearranged Tcra locus in αβ T lymphocytes. Interestingly, Eα is essential for the normal expression of the rearranged Tcrd locus in γδ T lymphocytes. In this review, the current knowledge about the regulation of Tcra/Tcrd germline transcription and gene segment rearrangement during thymocyte development and the possible mechanisms for transcription of the rearranged Tcra locus in mature αβ T lymphocytes are discussed. The knowledge of the detailed mechanisms involved in the regulation of transcription at the Tcra/Tcrd locus by distant enhancers is important to understand the cases in which deregulation this process resulta in disease.

Highlights

Two other Tcra/Tcrd regulatory elements have been recently described (Figure 2): 1) two binding sites for CTCF located upstream of the Trdv4 gene segment, INT1/2, that creates a functionally relevant chromatin loop with TEAp in DN2/3a thymocytes to increase the Tcrd and Tcra repertoires (see below), and 2) a new transcriptional enhancer located between the Traj3 gene segment and Cα, called E3 ́-Jα, that is active in thymic and peripheral αβ T cells as assessed using transgenic mice [28,42]
During thymic T-cell development (Figure 1), early T-cell progenitors (ETP) arising from fetal liver or bone marrow enter to the thymus, where they mature progressively through different stages that can be distinguished based on the expression of the CD4 and CD8 surface markers: CD4-CD8- double-negative (DN) thymocytes, immature single-positive (ISP) CD8+ thymocytes, CD4+CD8+ doublepositive (DP) thymocytes, and CD4+ or CD8+ single-positive (SP) thymocytes [1]
The loci that encode for the TCR chains are composed of dispersed variable (V), diversity (D), and joining (J) gene segments that are rearranged during thymocyte development by a process known as V(D)J recombination to generate a gene configuration capable of expressing the functional receptors, TCRαβ or TCRγδ, on the cell membrane [4,5]

Summary

Introduction

Two other Tcra/Tcrd regulatory elements have been recently described (Figure 2): 1) two binding sites for CTCF located upstream of the Trdv4 gene segment, INT1/2, that creates a functionally relevant chromatin loop with TEAp in DN2/3a thymocytes to increase the Tcrd and Tcra repertoires (see below), and 2) a new transcriptional enhancer located between the Traj3 gene segment and Cα, called E3 ́-Jα, that is active in thymic and peripheral αβ T cells as assessed using transgenic mice [28,42]. The deleted Tcrd locus in DP and SP thymocytes, and in αβ T lymphocytes, is represented as a separate circularized DNA fragment containing the rearranged Tcrd and several unrearranged Trav/Trdv and Traj gene segments produced as a consequence of a Tcra VJ recombination.

Results

Conclusion