Somatic Variation of T-Cell Receptor Genes Strongly Associate with HLA Class Restriction

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Somatic Variation of T-Cell Receptor Genes Strongly Associate with HLA Class Restriction

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Title: Somatic Variation of T-Cell Receptor Genes Strongly Associate with HLA Class Restriction
Author: Klarenbeek, Paul L.; Doorenspleet, Marieke E.; Esveldt, Rebecca E. E.; van Schaik, Barbera D. C.; Lardy, Neubury; van Kampen, Antoine H. C.; Tak, Paul P.; Plenge, Robert M.; Baas, Frank; de Bakker, Paul I. W.; de Vries, Niek

Note: Order does not necessarily reflect citation order of authors.

Citation: Klarenbeek, 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.
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Abstract: Every 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.
Published Version: doi:10.1371/journal.pone.0140815
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627806/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845145
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