Human Memory T cells show differential metabolic preferences

Abstract

Abstract Metabolic reprogramming regulates survival and function of immune cells, including T cells. Previous studies revealed that memory T cells are quiescent populations that primarily use OXPHOS for their metabolic needs. However, antigen rechallenge induces metabolic reprogramming including the engagement of aerobic glycolysis in which glucose is converted into lactate rather than oxidized into mitochondria. Here, we compared the metabolic characteristics of human naïve and memory T cells (TCM, TEM, and TEMRA) that are characterized by the cell surface proteins CCR7, and CD45RA. T cells were enriched from human PBMC samples, and then the subsets were sorted by flow cytometry. RNA-seq libraries constructed from each population were sequenced. Comparison of metabolism related transcript levels of the subsets revealed a distinct metabolic state in each cell type. Seahorse assays, mitochondrial staining flow cytometry assays and the SCENITH (Single Cell ENergetIc metabolism by profil Ing Translation in Hibition) assays were performed to assess the metabolisms of the individual populations. Our data indicated that resting CD4 and CD8 memory T cell populations have higher glycolytic and fatty acid capacity than the naïve T cells, consistent with the RNA-seq data. Resting naïve T cells depend on mitochondrial ATP production more than the memory T cells. However, when the cells are stimulated, the glycolytic capacity increased in all cell types and mitochondrial dependence decreased without a significant difference between subsets. Overall, our data highlights how memory T cell subsets retain greater metabolic capacity than naive T cell, potentially contributing to more efficient secondary responses.