Chromosomal excision of TCRd chain genes is dispensable for ab T cell lineage commitment

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