INFLUENCE OF CODING REGION POLYMORPHISM ON THE PERIPHERAL EXPRESSION OF A HUMAN TCR V-BETA-GENE

A number of human TCR Vbeta gene segments are reported to be polymorph ic, with alleles differing by one or a small number of amino acid subs titutions. In the absence of detailed structural information regarding the interaction of specific positions in the TCR with Ag or MHC, the significance of such variation is difficult to assess. In this report the relative use of the two common alleles of the human Vbeta6.7 gene, 6.7a and 6.7b, which differ by two non-conservative amino acid substi tutions, and the use of two common alleles of the Vbeta12.2 gene, whic h differ by only silent substitutions, were measured in PBL derived fr om individuals heterozygous for these alleles. Equal use of Vbeta12.2 alleles was observed, consistent with the inability of selection mecha nisms to discriminate between the products of these alleles that are i ndistinguishable at the amino acid level. However, statistically signi ficant skewing in the use of Vbeta6.7 alleles was observed in 15 of 16 individuals studied. Expression levels for each allele ranged from 16 to 84% of the total Vbeta6.7 signal in heterozygous individuals, with either the 6.7a or the 6.7b allele predominant in different individua ls. Based on segregation studies in families, it seems unlikely that o ther unidentified polymorphism in the TCRbeta locus, such as in the Vb eta6.7 promoter, was responsible for the differential allele expressio n. Family studies provided no evidence for an association between spec ific HLA haplotypes and Vbeta6.7 allele use. These results indicate th at even modest allelic variation in human TCR Vbeta coding regions can have a significant impact on the expression of human Vbeta genes in t he peripheral repertoire.