Human T-cell antigen receptor (TCR) delta-chain locus and elements responsible for its deletion are within the TCR alpha-chain locus

Abstract

Individual T cells express the CD3 molecule in association with alternative gamma delta or alpha beta heterodimeric T-cell receptors (TCRs). T-cell precursors and occasional gamma delta-expressing T cells in humans possess an unexpected 2.0-kilobase (kb) mRNA in which a tandemly repeated motif, TEA (T early alpha), has been spliced to the constant (C alpha) region. Long-range pulsed-field gel mapping as well as molecular cloning showed that TEA is located immediately 5' to the most upstream joining (J alpha) segment of the TCR alpha-chain locus. The TCR delta-chain locus is immediately 5' to TEA, and diversity (D delta) gene segments, J delta, C delta, and TEA are linked within 35 kb. The human TCR delta locus conserves a 12/23-base-pair (bp) spacer paradigm in which J delta possesses a 12-bp and V delta a 23-bp spacer, while the D delta segments have a 12 bp-D delta-23 bp spacer motif. Considerable TCR delta diversity can be generated despite the predominant use of one V delta and one J delta segment. Two D delta segments, D delta 1 and D delta 2, are 9 and 13 bp long, are frequently recombined as D delta 1-D delta 2, and reveal exonucleolytic trimming with extensive N-segment addition. A gamma delta clonal T cell possessed an effective VDDJ delta rearrangement and an intermediate DDJ delta rearrangement, arguing that the TCR delta locus displays allelic exclusion. Specific rearranging elements that delete the delta locus, delta Rec and psi J alpha, were mapped and found to separate the delta locus from the alpha locus. The delta locus including D delta 1-D delta 2-J delta 1-C delta-TEA was deleted in mature, alpha beta-expressing T cells, whereas V delta 1 was frequently retained. The location of the delta locus within the alpha locus may necessitate an exclusive choice between delta or alpha expression.