SYSTEMATIC STUDY OF HUMAN ALPHA-BETA-T-CELL RECEPTOR V-SEGMENTS SHOWS ALLELIC VARIATIONS RESULTING IN A LARGE NUMBER OF DISTINCT T-CELL RECEPTOR HAPLOTYPES

The variation of the alphabeta T cell receptor (TCR) results mainly from rearrangements of germ-line V, D and J elements combined with the processes of N- and P-region addition. In addition to this extensive diversity, diallelic polymorphism is also recognized in V regions of beta loci. Four such polymorphisms have previously been defined, but the full extent of such variation has not yet been established. To investigate allelic polymorphism, we used a strategy based on V locus-specific polymerase chain reaction and single-strand conformation polymorphisms. Studying the two Vbeta2 loci and the Valpha8.1 locus, we found that all exhibited a coding polymorphism. One of the Vbeta2 loci proved to be the first multiallele segment to be recognized, with three common variants. The second Vbeta2 locus, for which none of the two alleles has been identified in cDNA, appeared in fact to be a Vbeta orphon, in abnormal location on the chromosome 9. A yeast artificial chromosome containing part of the TCRB locus allowed us to place the first Vbeta2 segment on the known map to define haplotypes with two other polymorphic segments: Vbeta1 and Vbeta6.7. Multiple distinct haplotypes result from combinations between these polymorphic loci, showing that Vbeta regions are highly variable between individuals. Two alleles exist at the Valpha8.1 segment and both are expressed. This represents the first example of a frequent coding polymorphism for TCRA gene. The distribution of allele frequencies for these segments suggest the action of balancing selection. These data add a further dimension to TCR polymorphism and suggest new candidates to explore TCR-encoded susceptibility to autoimmune diseases.