Revision of T cell receptor a chain genes is required for normal T lymphocyte development

To become mature alpha beta T cells, developing thymocytes must first assemble a T cell receptor (TCR) beta chain gene encoding a TCR beta chain that forms a pre-TCR. These cells then need to generate a TCR alpha chain gene encoding a TCR alpha chain, which, when paired with the TCR beta chain, forms a selectable alpha beta TCR. Newly generated Via rearrangements that do not encode TCR alpha chains capable of forming selectable alpha beta TCRs can be excised from the chromosome and replaced with new Via rearrangements. Such replacement occurs through the process of TCR alpha chain gene revision whereby a V alpha gene segment upstream of the VJ alpha rearrangement is appended to a downstream J alpha gene segment. A multistep, gene-targeting approach was used to generate a modified TCR alpha locus (TCR alpha(sJ)) with a limited capacity to undergo revision of TCR alpha chain genes. Thymocytes from mice homozygous for the TCR alpha(sJ) allele are defective in their ability to generate an alpha beta TCR. Furthermore, those thymocytes that do generate an alpha beta TCR have a diminished capacity to be positively selected, and TCR alpha(sJ/sJ) mice have significantly reduced numbers of mature alpha beta T cells. Together, these findings demonstrate that normal T cell development relies on the ability of developing thymocytes to revise their TCRa chain genes.