Defining heterogeneity and biological signature in human effector memory CD8+ T cells expressing different levels of IL-7 receptor alpha by high-dimensional analysis

Abstract

Abstract Human effector memory (EM) CD8+ T cells have been divided into a small number of subsets based on the expression of a single or a few cell surface molecules. Previously, we showed the presence of human EM CD8+ T cell subsets expressing IL-7 receptor alpha chain (IL-7Rα) high and low that have different characteristics like the expression of cytotoxic molecules, cytokines, co-stimulatory molecules, and DNA methylation. However, it is unknown whether IL-7Rα can serve as a key molecule in defining a comprehensive landscape of heterogeneity in human EM CD8+ T cells as determined by high-dimensional single cell analysis. Here we addressed this question by performing Cytometry by Time-Of-Flight (CyTOF) and single-cell RNA-seq (scRNA-seq) analysis on human EM CD8+ T cells and analyzing such data using computational algorithms. IL-7Rα had diverse, but organized, expressional relationship in EM CD8+ T cells with molecules related to gene regulation, effector function, survival, and migration, which rendered an immune landscape defining heterogeneous cell subsets. The differential expression of these molecules likely has biological implications as we found in vivo signatures of transcription factors and homeostasis cytokine receptors, including T-bet and IL-7Rα, as well as the possible alterations of EM CD8+ T cell heterogeneity defined by these molecules in lupus patients. Our findings indicate the existence of heterogeneity in human EM CD8+ T cells as defined by distinct but organized expression patterns of multiple molecules in relationship to IL-7Rα and possible biological significance of differential expression of such molecules in modulating downstream events and pathologic conditions.