T cell receptor V-segment frequencies in peripheral blood T cells correlate with human leukocyte antigen type.

Abstract

SummaryWe compared T cell receptor (TCK) V-segment frequencies in human leukocyte antigen (HLA) identical siblings to sibling pairs who differ at one or both HLA haplotypes using four Vflspecific and one Vot-specific monoclonal antibody. In every one of nine families HLA-identical sibs had the most similar patterns of V-segment frequencies in their peripheral blood, whereas totally mismatched sihs were, in general, the most dissimilar; HLA haploidentical sibs tended to be intermediate between the two groups. The degree of similarity among HLA-identical fibs was comparable to that observed among three pairs of identical twins suggesting that HLA is the major genetic component influencing TCK V-segment frequency. Consistent with this observation, it was found that the frequency of T ceils expressing particular Vfl segments was skewed towards either CD4 + or CD8 + cells indicating that T cells expressing some Vfl genes may be positively selected primarily by class I or class II major histocompatibility complex proteins. Finally, it was observed that individuals who express the HLA class I specificity, B38, tend to express high levels of Vcz2.3 + cells among their CD8 § T cells. These observations represent definitive proof that human V-segment frequencies are profoundly influenced by the HLA complex. I n mice, the H-2 complex plays a prominent role in determining TCR V-segment frequencies. Both class I and class II antigens influence the pattern of V-segment frequencies. This occurs either by negative sdection (1-5) where CD4 + 8 + thymocytes expressing TCK with high affinity for self MHC molecules plus endogenous peptide are clonaUy deleted or, by positive selection (6-13) where thymocytes with TCR expressing low affinity for the complex are permitted to mature into T cells capable of recognizing "foreign" peptides presented by self MHC molecules. A similar effect on human V-segment frequencies by the HLA complex has been difficult to demonstrate presumably because of the genetic heterogeneity and complexity of the HLA region in the outbred human population. In order to circumvent these difficulties we have analyzed V-segment frequencies within nine large families consisting of multiple siblings. In particular we have compared the V-segment frequency patterns of HLA-identical siblings to sibling pairs who differ at one or both HLA haplotypes. This experimental approach has allowed us to demonstrate the influence of HLA genes on V-segment frequencies in human peripheral blood T cells. Materials and MethodsCell Preparation. Peripheral blood was obtained from normal volunteers. Mononuclear cells were isolated by Ficoll/Hypaque gradient separation and T cells were isolated using magnetic beads to which anti-CD2 mAb was covalently coupled (Dynal Inc., Great Neck, NY). After overnight incubation, the spontaneously released cells were separated into CD4 + and CD8 + cells using magnetic beads covalently coupled with anti-CD4 and anti-CD8. The CD4 + and CDS+ cells obtained were >98% pure. Cold blood cells were purified by ...

Analysis of the T‐Cell Receptor Vβ Usage in Monozygotic and Dizygotic Twins Living in a Plasmodium falciparum Endemic Area in West Africa

“…However, in contrast to mice, the effect of various genetic elements on the development of the TCR repertoire in man has been difficult to demonstrate. Earlier studies using small groups of HLA-identical or non-identical siblings or family studies have suggested that HLA genes can influence the human Vb repertoire [8,12,13,29]. In the present study, when examining 10 pairs of Mz and nine pairs of Dz twins, the mean within-pair difference was significantly lower for the Mz than for the Dz pairs, suggesting a major genetic influence on the TCR Vb repertoire expression.…”

“…Recent studies of Mz twin pairs have revealed a higher concordance in TCR a and b usage than other siblings or unrelated individuals, suggesting that inter-individual differences of the peripheral TCR repertoire results largely from genetic factors [8][9][10][11][12]. Previous studies have demonstrated that HLA genes can profoundly influence the TCR Vb repertoire [13,14]. However, these and more recent studies [15] also suggested that other genetic factors can play a role in the development of the TCR repertoire.…”

Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

“…Nevertheless, biases in the overall peripheral Vβ repertoire between unrelated individuals who share the same HLA alleles are rare (31), which argues against a general role for preferential pairwise TCR-MHC interaction motifs. Perhaps this is partly explained by the complexity of repertoire selection against up to 12 distinct MHC allotypes (assuming 6 heterozygous loci); however, one might still expect a general bias in Vβ selection across specific MHC allotypes and this has only been evident in twin studies (31).…”

“…Nevertheless, biases in the overall peripheral Vβ repertoire between unrelated individuals who share the same HLA alleles are rare (31), which argues against a general role for preferential pairwise TCR-MHC interaction motifs. Perhaps this is partly explained by the complexity of repertoire selection against up to 12 distinct MHC allotypes (assuming 6 heterozygous loci); however, one might still expect a general bias in Vβ selection across specific MHC allotypes and this has only been evident in twin studies (31). On the other hand, repeated selection of particular V regions and/or D/J and N-region genetic elements in antigenspecific responses indicates that these regions must encode exquisite interactions to enable TCR interaction with self-MHC complexed to specific peptides (30,32).…”

Population study of T cell receptor Vβ gene usage in peripheral blood lymphocytes: differences in ethnic groups

“…Using a restricted number of V/f and V/f-spcciHc MoAbs. GulwaniAkolkar and collcagties demonstrated the influence of human leucocyte antigens (MHC) on V^ gene usage in famiiy studies [6]. and more recent resuits with monozygotic twins also suggest that the predominant influence shaping the repertoire is gencticaily predetermined [25].…”