Alternative Splicing Restricts Translation of Rearrangements at the T-cell Receptor 6/a Locus

Lymphocytes expressing a/3 or-yS T-cell receptors (TCR) represent distinct T-cell populations. Because TCRS genes lie within the TCRa locus, the rearrangement processes, transcription, and translation of TCRS or TCRa variable domain exons require tight regulation. Human precursor B-cell leukemias (eg, the REH cell line) constitute an interesting model to study TCRSla recombination because they rearrange TCRS/(u loci along a hierarchically ordered pathway in which VS2DS3 segments are joined to the Ju cluster. We now show for REH cells that chimeric TCRS/a variable domain exons are posttranscriptionally modified by alternative HE ANTIGEN BINDING DOMAINS of Igs as well as T-cell receptors (TCRs) are generated during lympho-cyte differentiation by the assembly of variable (V), joining (J), and in some loci, diversity (D) gene segments. Additional variability stems from imprecise V(D)J joining, ie, loss of germline nucleotides through exonucleolytic activity, addition of template-derived P (palindromic) elements, and insertion of template-independent N regions mediated by terminal deoxynucleotidyl transferase. Two crucial components of this rearrangement process are the recombinase activating genes, RAG1 and RAG2.I.' Human T-lymphocytes can be divided into two distinct subsets based on their cell surface expression of antigen receptor molecules. The majority of peripheral blood T-cells express a CD3-associated ap TCR. A smaller T-cell subset of still insufficiently defined function expresses a CD3-associated yS TCR.'.4 Although TCRyS cells appear in the thy-mus during fetal ontogeny several days before T C R ~ U , ~ , ~ it remains unclear whether these two cell types represent distinct lineages or whether TCRaP cells are derived from thymocytes that have failed to recombine their TCRy and TCRS loci productively. This problem is highlighted by the fact that the TCRS locus is nested within the TCRa locus between the V a and Ja region gene segments. One hypothe-sis' holds that a@ lineage-committed T-cell precursors delete the unrearranged TCRS locus on both alleles under the subtle control of TCRa silencedenhancer and T early a sequences T The puhlication costs ofthis article were defrayed in part by page charge payment. This article must therefi~re be hereby marked "advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this .fizct. via a recombination between the SREC and $Ja elements, thereby precluding TCRS usage.7-" On the other hand, re-combined TCRS sequences have been found on the extra-chromosomal excision circles that are generated during the deletion of the TCRS Iocus.".'~ In addition, rearranged TCR6 elements on one and recombined …