T-cell development in the absence of the pre-T-cell receptor

Abstract

The development of pre-T-cells with productive T-cell receptor β (TCRβ) rearrangements can be furthered by each of the pre-T-cell receptors (pre-TCR), the αβ TCR as well as the γδ TCR, albeit by distinct mechanisms. While the γδ TCR affects CD4⁻8⁻ precursor cells irrespective of their TCRβ rearrangement status both the pre-TCR and the αβ TCR select only cells with productive TCRβ genes for expansion and maturation. The αβ TCR is much less effective than the pre-TCR because of the paucity of TCRα proteins in TCRβ positive precursors.

Introduction

During development of αβ T-cells in the thymus, most T-cell receptor (TCR) genes rearrange in temporal order such that most TCRβ rearrangement occurs before TCRα rearrangement 1, 2. Over the years it became clear that the products of the rearranged genes, i.e. the TCRβ and TCRα chains, have an important role in controlling T-cell development: The first produced TCRβ chain covalently binds to the pre-TCRα (pTα) chain 3, 4and forms the pre-TCR that rescues from programmed cell death CD4⁻8⁻44⁻25⁺ cells that have succeeded in TCRβ chain rearrangement. The selected cells assume the CD4⁻8⁻44⁻25⁻ phenotype [5], proliferate extensively and eventually become CD4⁺8⁺ cells that bear the αβ TCR on the cell surface while expression of the pTα is terminated 6, 7. The CD4⁺8⁺ expressing cells are programmed to die unless the αβ TCR binds to thymic MHC molecules and cells are rescued from cell death once more and eventually become mature T-cells that leave the thymus 8, 9.

Experiments in pre-TCR deficient TCRβ^−/− or pTα^−/− mice had shown that the pre-TCR, while having an important function in generating large numbers of CD4⁺8⁺ cells from CD4⁻8⁻ precursors was likely not to be the only TCR able to mediate these events since both types of mutant mice still contained significant though reduced numbers of CD4⁺8⁺ thymocytes 6, 10. In fact the origin of the CD4⁺8⁺ cells in TCRβ^−/− mice was obscure and the possibility was discussed that they may belong to the γδ lineage [10]. In pTα^−/− mice, however, some of the CD4⁺8⁺ cells expressed αβ TCRs on the cell surface and could undergo positive selection to become mature T-cells, i.e. they belonged to the αβ lineage. It is shown here that not only the pre-TCR but both the γδ TCR as well as the αβ TCR can further the differentiation of CD4⁻8⁻25⁺ pre-T-cells albeit by distinct mechanisms.