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
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, United States of America; Department of Clinical Immunology and Rheumatology, Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Laboratory for Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Department of Clinical Immunology and Rheumatology, Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Laboratory for Genome Analysis, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
PLoS One. 2015 Oct 30;10(10):e0140815. doi: 10.1371/journal.pone.0140815. eCollection 2015.
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.
为维持健康的免疫系统，每个人体内都携带大量的CD4+辅助性T细胞和CD8+细胞毒性T细胞。编码T细胞受体（TCR）的基因组位点发生的体细胞VDJ重组是T细胞发育过程中的关键步骤，但单个T细胞如何决定成为CD4+或CD8+ T细胞却知之甚少。为评估TCR序列变异对CD4+/CD8+谱系分化的影响，我们对从健康供体分离的初始T细胞中重排的α和β链TCR进行了测序，并研究了CD4+和CD8+ T细胞亚群中的基因片段使用情况和重组模式。我们的数据表明，大多数V和J基因片段在初始CD4+和CD8+亚群中存在强烈偏向性，一些片段使成为CD4+（或CD8+）的几率增加了五倍。这些V和J基因关联在个体间具有高度可重复性，且独立于经典的HLA基因型，解释了观察到的CD4+与CD8+倾向差异的约11%。此外，我们在α和β链中均发现互补决定区3（CDR3）的静电荷存在强烈的独立关联，其中带正电荷的CDR3与CD4+谱系相关，带负电荷的CDR3与CD8+谱系相关。我们的研究结果表明，TCR不同部位的体细胞变异以主要累加的方式影响T细胞谱系分化。这一概念有助于阐明TCR-肽-HLA复合物的某些结构特征如何影响胸腺选择。
