Somatic Variation of T-Cell Receptor Genes Strongly Associate with HLA Class Restriction
Klarenbeek, Paul L.
Doorenspleet, Marieke E.
Esveldt, Rebecca E. E.
van Schaik, Barbera D. C.
van Kampen, Antoine H. C.
Tak, Paul P.
Plenge, Robert M.
de Bakker, Paul I. W.
de Vries, NiekNote: Order does not necessarily reflect citation order of authors.
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CitationKlarenbeek, P. L., M. E. Doorenspleet, R. E. E. Esveldt, B. D. C. van Schaik, N. Lardy, A. H. C. van Kampen, P. P. Tak, et al. 2015. “Somatic Variation of T-Cell Receptor Genes Strongly Associate with HLA Class Restriction.” PLoS ONE 10 (10): e0140815. doi:10.1371/journal.pone.0140815. http://dx.doi.org/10.1371/journal.pone.0140815.
AbstractEvery person carries a vast repertoire of CD4+ T-helper cells and CD8+ cytotoxic T cells for a healthy immune system. Somatic VDJ recombination at genomic loci that encode the T-cell receptor (TCR) is a key step during T-cell development, but how a single T cell commits to become either CD4+ or CD8+ is poorly understood. To evaluate the influence of TCR sequence variation on CD4+/CD8+ lineage commitment, we sequenced rearranged TCRs for both α and β chains in naïve T cells isolated from healthy donors and investigated gene segment usage and recombination patterns in CD4+ and CD8+ T-cell subsets. Our data demonstrate that most V and J gene segments are strongly biased in the naïve CD4+ and CD8+ subsets with some segments increasing the odds of being CD4+ (or CD8+) up to five-fold. These V and J gene associations are highly reproducible across individuals and independent of classical HLA genotype, explaining ~11% of the observed variance in the CD4+ vs. CD8+ propensity. In addition, we identified a strong independent association of the electrostatic charge of the complementarity determining region 3 (CDR3) in both α and β chains, where a positively charged CDR3 is associated with CD4+ lineage and a negatively charged CDR3 with CD8+ lineage. Our findings suggest that somatic variation in different parts of the TCR influences T-cell lineage commitment in a predominantly additive fashion. This notion can help delineate how certain structural features of the TCR-peptide-HLA complex influence thymic selection.
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