The Influence of Non‐HLA Genes on the Human T‐Cell Receptor Repertoire

We previously demonstrated a central role for HLA genes in determining the T-cell receptor (TCR) repertoire. However, these studies also suggested that other genetic factors might also play a role in the development of this repertoire. In order to assess the role of non-HLA genes in the development of the TCR repertoire, we have analysed and compared the TCR repertoires of individuals in three families consisting of both monozygotic twins as well as an HLA-identical sib. TCR repertoire analysis was performed with both V-segment-specific MoAb and the polymerase chain reaction using TCRBV-segment-specific oligonucleotide primers. We observed that in every case the TCR repertoires of identical twins were more similar to each other than to their HLA-identical sib. Furthermore, in one family we were able to show by genotype analysis that most of the differences in repertoire between the identical twins and their HLA-identical sib were caused by polymorphisms in the TCR genes that influence expression levels. These studies document an important role for non-HLA genes in determining the TCR repertoire in man and raise the possibility that such TCR polymorphisms may play a significant role in determining disease susceptibility.