Integrating T cell receptor features with gene expression profiles to define T cell specificity and differentiation

摘要 本提案的目的是确定T细胞受体（TCR）序列与 在人类T细胞景观中的转录谱。这项工作是由我们最近的发展， CoNGA算法是一种整合TCR和基因表达（格克斯）数据集的图论方法， 并且通过技术进步使得能够以高生产量并行地对两种特征进行轮廓描绘。 提交以回应特别关注通知NOT-AI-21-011（“现有数据集的二次分析 促进免疫介导和传染病研究”），我们的建议汇集了一个团队， 计算生物学家和免疫学家的成功合作记录。我们的目标是应用 CoNGA在不同的T细胞数据集上定义标志性TCR特征及其相关表型， 人类T细胞在第一个目标中，我们将识别，获取，预处理和标准化所有大型，公开 可用的单细胞数据集，其特征在于关联的基因表达和配对的TCR序列信息。我们 然后将在这些单独的数据集上运行CoNGA管道，将结果与可用的研究相关联 元数据，并使这些结果可供下载。在第二个目标中，我们将进行荟萃分析 T细胞受体序列和T细胞转录谱之间的关系 （1，000+供体和1，000，000+单个T细胞）。完成这里提出的工作将奠定 为人类T细胞景观的综合图谱奠定了基础，并为进一步研究提供了有价值的数据集。 开发分析工具和方法。通过CoNGA鉴定的T细胞特征和亚群将 提供了对单个数据集的新见解，同时也阐明了格克斯/TCR的全球格局 协变

ABSTRACT The objective of this proposal is to identify linkages between T cell receptor (TCR) sequences and transcriptional profiles across the human T cell landscape. This work is enabled by our recent development of the CoNGA algorithm, a graph theoretic approach that integrates TCR and gene expression (GEX) datasets, and by technological advances that have made it possible to profile both features in parallel at high throughput. Submitted in response to Notice of Special Interest NOT-AI-21-011 ("Secondary Analysis of Existing Datasets for Advancing Immune-mediated and Infectious Disease Research"), our proposal brings together a team of computational biologists and immunologists with a track record of successful collaboration. Our goal is to apply CoNGA on diverse T cell datasets to define the landmark TCR features and their correlated phenotypes in human T cells. In the first Aim, we will identify, acquire, pre-process, and standardize all large, publicly available single-cell datasets that feature linked gene expression and paired TCR sequence information. We will then run the CoNGA pipeline on these individual datasets, correlate the results with available study metadata, and make these results available for download. In the second Aim, we will perform a meta-analysis of the relationship between T cell receptor sequence and T cell transcriptional profile across the entire dataset (1,000+ donors and 1,000,000+ individual T cells). Completion of the work proposed here will lay the groundwork for a comprehensive atlas of the human T cell landscape and provide a valuable dataset for further development of analytical tools and methods. T cell features and sub-populations identified by CoNGA will provide new insight into the individual datasets while also illuminating the global landscape of GEX/TCR covariation.