Chromosomal excision of TCRδ chain genes is dispensable for αβ T cell lineage commitment

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Abstract
TCRβ, δ and γ chain genes are assembled and expressed in double-negative thymocytes prior to αβ or γδ T cell lineage commitment. Thus, cells committed to the αβ T cell lineage can possess completely assembled TCRδ and/or TCRγ chain genes. However, these genes are not expressed. TCRγ chain gene expression may be silenced through the activity of a cis-acting silencer element. In the TCRα/δ locus, the TCRδ genes lie between the Vα and Jα gene segments, which rearrange by deletion. Moreover, Vα to Jα rearrangements occur on both alleles in essentially all developing αβ T cells. Consequently, both TCRδ chain genes are excised from the chromosome and placed on extrachromosomal circles in mature αβ T cells. It has been proposed that this excision process is important for silencing TCRδ gene expression and permitting αβ T cell lineage commitment. A gene-targeting Cre–loxP strategy was used to invert a 75-kb region of the TCRα/δ locus encompassing all the Jα gene segments, generating the TCRα/δI allele. Initial Vα to Jα rearrangements on the TCRα/δI allele occur by inversion, resulting in chromosomal retention of TCRδ chain genes. These TCRδ chain genes can be productively rearranged and are expressed at levels similar to TCRδ chain genes in γδ T cells. However, αβ T cell development appears unperturbed in TCRα/δI/I mice. Thus, excision of TCRδ genes from the chromosome per se is not required for commitment of developing lymphocytes to the αβ T cell lineage.