However, it remains unknown to what extent HLA polymorphism affects TCR repertoire diversity in humans. These data, together with structural studies of the TCR-MHC interface, have provided key insights into how the TCR binds MHC and peptide. MHC restriction is the cornerstone of T cell recognition, and prior reports have assessed the effect of the presence of specific MHC alleles on TCR V gene usage and repertoire sharing. Accordingly, considerable effort has been devoted to understanding how MHC genetic variation impacts the TCR repertoire. TCR diversity can determine how efficiently one rejects pathogens such as viruses, and potentially cancer cells. Those TCRs that survive thymic selection are responsible for mounting productive immune responses through continuous interaction with self and foreign peptides bound to MHC molecules. TCRs that fail to bind to peptide-MHC complexes and those that bind too strongly are eliminated. Whether a particular TCR joins the periphery depends on its behavior during thymic selection, in which TCRs interact with both self peptide and MHC. The CDR3 regions of the TCR are primarily responsible for interacting with the peptide presented by MHC, with the potential diversity of CDR3β exceeding that of CDR3α. In the thymus, VDJ recombination facilitates random rearrangement of the complementary determining region 3 (CDR3) within the TCR α and β loci, followed by random nucleotide insertion and deletions at junction sites. This diversity, estimated to exceed 10 6 sequences in humans, is shaped by stochastic and genetic effects in conjunction with continuous immunological challenges throughout life. If these data can be extended to HTLV-1-infected patients studied in vivo, the Th cell repertoire specific for HTLV-1 env may prove very heterogenous, with important implications for vaccine development.The large sequence diversity of the TCR repertoire is a hallmark of the adaptive immune system, and varies markedly across individuals. Furthermore, by sequencing the TCR genes, we identified clones with identical Vbeta gene usage which differed in hypervariable regions (CDR3), indicating their derivation from independent precursors and contributing to overall clonal heterogeneity. Therefore evaluation of the clonal composition of a T-cell line gives a snapshot of the dominant clones at the time of analysis, and does not tell the whole picture of the antigen-specific ensemble. Clones in fact may be up- and down-regulated and clonotypes undetectable at one time point can emerge upon subsequent restimulation. Diverse Vbeta genes were used by the same line tested at different times, suggesting that clonal composition of an antigen-specific T-cell line is not constant in vitro. We found that a diverse repertoire for HTLV-1 env could be triggered in vitro. Fluctuations in the V beta gene usage were determined by comparing the TCR Vbeta gene profiles of T-cell lines at different times. Clonal heterogeneity was determined by analysing the T-cell receptor (TCR) Vbeta gene usage and by sequencing the hypervariable regions of the TCR genes. The naive T-helper (Th) repertoire specific for HTLV-1 envelope (env) has been examined on antigen specific T-cell lines and clones from non-immune individuals.
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