SummaryOne of the causes of variations in the expressed human T cell receptor (TCR) BV (V~) repertoire is genetic variation in the germline DNA. Herein evidence is provided that allelic polymorphism may affect recombination frequency for a specific V gene. Two alleles of the TCR BV3 differ only at a single nucleotide position (C/T) within the 23-bp spacer region of the recombination signal sequence. These alleles are associated with variable percentages of BV3 cells in the peripheral blood, as shown in families and in unrelated normal donors. Individuals homozygous for allele 2 have a mean of 8.1% BV3 cells, heterozygous individuals have a mean of 4.7% BV3 cells, and homozygotes for allele 1 have a mean of 1.2% BV3 cells in CD3 § CD4 + peripheral blood T cells. Since the correlation is tight in unrelated individuals and other genetic differences were not found in the vicinity of BV3, we suggest that the spacer region sequence itself modifies recombination efficiency. This allelic system provides an example of a novel mechanism by which c/s-acting genetic elements may affect recombination in a natural in vivo system. T he vast diversity of TCR and immunoglobulins is created primarily by V(D)J recombination in maturing lymphocytes. As a result of this theoretically random process, a repertoire of highly diverse TCR is generated (1), but the observed repertoire in mature lymphocytes is skewed because of both genetic and environmental factors. Genetic control of the TCR repertoire is apparent because of highly similar profiles of TCR, Vot and V~ usage among monozygotic twins as opposed to unrelated individuals (2-6). Genes that influence the TCR repertoire include the MHC (2) and the TCR genes themselves. MHC genes mold the TCR repertoire because of recognition of peptide Ag in the context of MHC molecules. Thus, certain T cell subsets may be positively or negatively selected in the context of one MHC allele but not another.TCIL V gene segments are deleted in certain mouse haplotypes (7). Genomic deletions in the TCRBV locus also exist in humans (8) and directly affect the number of genomic V gene segments (9). In addition, a number of aUelic polymorphisms of TCR V gene exons have been described. Some of these result in null alleles (10, 11) and others result in different amino acid sequences at putative Ag/MHC or SAG-reactive sites (12)(13)(14)(15). It is also possible that TCR gene elements fail to rearrange efficiently because of structural constraints on some aspect of the recombinase machinery.This report describes a new type of polymorphism that can shape the TCR repertoire. AUelic variation in the TCRBV3 recombination signal sequence (R.SS) is associated with the level of BV3 gene segment utilization in the peripheral blood (formerly V~3, the new WHO-IUSIS recommended nomenclature is used throughout this manuscript. Bull. WHO 71:113-115, 1993). Variable expression of BV3 was first mapped to the TCRB locus in family studies and then shown to correlate with allelic variants of the BV3 RSS in unrelated individua...

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