TCR repertoire: size, diversity, and function

TCR 库：大小、多样性和功能

• 批准号: 10007349
• 负责人: Nan-ping Peter Weng
• 金额: $ 44.62万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10007349
• 关键词: Adult; Age; Amino Acids; Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Characteristics; Goals; High-Throughput Nucleotide Sequencing; Human; Immunity; Immunobiology; Life; Machine Learning; Maintenance; Measures; Memory; Methods; Mus; Population; Property; Regulatory T-Lymphocyte; Reporting; Role; Structure; Study Subject; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; T-cell receptor repertoire; Thymus Gland; Visit; aged; alpha-beta T-Cell Receptor; base; follow-up; immune function; in vivo; indexing; longitudinal analysis; machine learning algorithm; pathogenic virus; precision medicine; transcriptome sequencing

Understanding how the size and content of TCR reprotire and their changes with age remains a critical challenge in immunobiology. Here, we report a longitudinal analysis of TCR repertoire of human T cells and subsets from 30 healthy adults aged from 25 to 85 at first visit and an average of 9-year follow-up as second visit by RNAseq. From analysis of combined 2.0 x 108 nave and memory CD4+ and CD8+ T cells, we identified 1.1 x 106 and 2.8 x 106 unique TCR and TCR sequences. We found despite a general reduction of nave TCR repertoire size with age, the in vivo change of nave TCR repertoire (species richness and D50 index) in the study subjects was highly individualized. Reduction of nave CD4+ and CD8+ TCR repertoires occurred at all adult age from 30-90 but altered expansion of naive CD8+ T cells found in later years, probably due to cumulated unbalanced homeostatic expansion over the years of life. A striking age change is increased similarity of TCR repertoire between nave and memory CD4+ and CD8+ T cells, suggesting nave TCR repertoires may be also selected. These findings provide a framework of TCR and TCR diversity and their changes with age in CD4+ and CD8+ nave and memory T cells. Thymic regulatory T cells (tTreg) are critical in maintenance of normal T cell immunity and tolerance. The role of TCR in tTreg cell selection remains incompletely understood. Here we assessed TCR and TCR sequences of tTreg and conventional thymic CD4+ T (Tconv) cells by high throughput sequencing. We identified TCR sequences that were unique to either tTreg or Tconv cells and found that these were distinct as recognized by machine learning (ML) algorithm and by preferentially used amino acid trimers in CDR3 of tTreg cells. In addition, a proportion of TCR sequences expressed by tTreg were also found in Tconv cells, and ML classified the great majority of these shared TCR sequences as characteristic of Tconv and not tTreg cells. These findings identify two populations of tTreg, one in which Treg fate is associated with unique properties of the TCR, and another with TCR properties characteristic of Tconv cells for which tTreg fate is determined by factors beyond TCR sequence.

了解TCR的大小和含量如何随着年龄的增长而变化，仍然是免疫生物学中的一个关键挑战。在这里，我们报告了30名年龄在25至85岁的健康成年人首次就诊时的人类T细胞和亚群的TCR库的纵向分析，并通过RNAseq进行了平均9年的随访作为第二次就诊。通过分析组合的2.0 x 108个初始和记忆CD 4+和CD 8 + T细胞，我们鉴定了1.1 x 106和2.8 x 106个独特的TCR和TCR序列。 我们发现，尽管随着年龄的增长，原始TCR库的大小普遍减少，但研究对象中原始TCR库（物种丰富度和D50指数）的体内变化是高度个体化的。幼稚CD 4+和CD 8 + TCR库的减少发生在30-90岁的所有成年年龄，但幼稚CD 8 + T细胞的扩增在以后几年中发现改变，可能是由于多年来累积的不平衡稳态扩增。 一个显著的年龄变化是初始和记忆性CD 4+和CD 8 + T细胞之间TCR库的相似性增加，表明初始TCR库也可以被选择。 这些发现提供了一个框架的TCR和TCR的多样性和他们的变化与年龄的CD 4+和CD 8+幼稚和记忆T细胞。 胸腺调节性T细胞（tTreg）在维持正常T细胞免疫和耐受中至关重要。TCR在tTreg细胞选择中的作用仍不完全清楚。在此，我们通过高通量测序评估了tTreg和常规胸腺CD 4 + T（Tconv）细胞的TCR和TCR序列。 我们鉴定了tTreg或Tconv细胞所特有的TCR序列，并发现这些序列是不同的，如机器学习（ML）算法和tTreg细胞的CDR 3中优先使用的氨基酸三聚体所识别的。此外，tTreg表达的一部分TCR序列也在Tconv细胞中发现，ML将这些共享的TCR序列中的绝大多数归类为Tconv细胞而不是tTreg细胞的特征。这些发现鉴定了两个tTreg群体，其中一个群体中Treg命运与TCR的独特性质相关，另一个群体中Treg命运与Tconv细胞的TCR性质特征相关，其中tTreg命运由TCR序列以外的因素决定。