T Cell Development in TCRβ Enhancer-Deleted Mice: Implications for αβ T Cell Lineage Commitment and Differentiation

Abstract

T cell differentiation in the mouse thymus is an intricate, highly coordinated process that requires the assembly of TCR complexes from individual components, including those produced by the precisely timed V(D)J recombination of TCR genes. Mice carrying a homozygous deletion of the TCRβ transcriptional enhancer (Eβ) demonstrate an inhibition of V(D)J recombination at the targeted TCRβ locus and a block in αβ T cell differentiation. In this study, we have characterized the T cell developmental defects resulting from the Eβ−/− mutation, in light of previously reported results of the analyses of TCRβ-deficient (TCRβ−/−) mice. Similar to the latter mice, production of TCRβ-chains is abolished in the Eβ−/− animals, and under these conditions differentiation into cell-surface TCR−, CD4+CD8+ double positive (DP) thymocytes depends essentially on the cell-autonomous expression of TCRδ-chains and, most likely, TCRγ-chains. However, contrary to previous reports using TCRβ−/− mice, a minor population of TCR γδ+ DP thymocytes was found within the Eβ−/− thymi, which differ in terms of T cell-specific gene expression and V(D)J recombinase activity, from the majority of TCR−, αβ lineage-committed DP thymocytes. We discuss these data with respect to the functional role of Eβ in driving αβ T cell differentiation and the mechanism of αβ T lineage commitment.

The Type 1 Cysteinyl Leukotriene Receptor Triggers Calcium Influx and Chemotaxis in Mouse αβ- and γδ Effector T Cells

“…GSE2287. Because ␥␦ T cells are the only T cells able to mature in Lat3YF mice, we compared their gene expression profile with that of wild-type ␥␦ T cells purified from TCR␤ enhancer-deficient mice (E␤ Ϫ/Ϫ mice) (13). These constitute a particularly appropriate control for ␥␦ T cells present in Lat3YF mice because they also matured in an environment deprived of ␣␤ T cells.…”

Temporal Predisposition to αβ and γδ T Cell Fates in the Thymus

“…However, a small fraction of them express TCRgd and enter the ab pathway through TCRgd selection. In the normal thymus, these cells may be outcompeted by b-selected cells and disappear before the DP stage (49), but they constitute the DP pool in TCRb-deficient mice or in Tg-gd mice in a RAGdeficient background (8,10,(19)(20)(21)(22)(23). As shown in this study and previously (25), a small fraction of their progeny will differentiate into gd cells, indicating that lineage commitment only occurs after TCR expression.…”

“…B6 CD45.1, B6 mice Tg for rearranged Vg1Jg4Cg4 and Vd6Dd2Jd1 chains (Tg-gd) (39), pTa-deficient mice, and TCRb enhancer (Eb)-deficient mice (23) were maintained in our animal facilities. All animal procedures were in compliance with the guidelines of the committee on animal experimentation of the Institut Pasteur and were approved by the French Ministry of Agriculture.…”

“…Notably, TCRgd can also mediate bselection-like differentiation to the DP stage. This is most evident in animals unable to express a functional pre-TCR, in TCRgd Tg mice in vivo (8,10,(19)(20)(21)(22)(23), and in cultures in which TCRgdexpressing progenitor cells are allowed to develop in vitro (24)(25)(26). Like b-selected DP cells, gd-selected DP cells silence TCRg gene expression and undergo TCRa rearrangements, indicating that they are bona fide ab-lineage cells (21).…”

Aberrant V(D)J cleavages in T cell receptor β enhancer- and p53-deficient lymphoma cells

“…The defect was more severe in the Vß-to-DßJß rearrangement. Thus, no TCRß was produced and no ·ß T lymphocytes developed in the Eß-deficient mice (11,12,19). It was also reported that the levels of Dß-Jß rearrangements were much more severely reduced than the levels of Dß and Jß signal ends in the Eß-deficient mice.…”