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Title:
Studying Cell Type-Specific T cell Metabolism Using Pathway- and Network-Based Approaches

Authors:
Martina Kutmon, Ella von Moeller and Jordy Gnanapragasam

Abstract:
Background: T cells play a crucial role in the immune system. This diverse group of immune cells takes on a variety of functions, from killing infected cells directly to helping other cells in their immune responses. Different T cell types have varying energy and metabolic requirements. While naïve T cells show lower activity levels, active and proliferating T cells have higher energy demands. In this research, cell-type specific RNA sequencing data from human blood samples was analyzed to deepen the understanding of the metabolic profiles of T cells. The overarching aim is to understand the interconnection of the molecular and metabolic processes governing T cell immunity.

Methodology: Seven T cell types were studied, namely naïve CD4+ and CD8+ T cells, memory CD4+ and CD8+ T cells, gamma delta (γδ) T cells, mucosal-associated T invariant (MAIT) cells and regulatory T (Treg) cells using cell-type specific transcriptomics data from the Human Protein Atlas. A pathway- and network-based approach was employed using R and Cytoscape to study the pathway activity levels, and a metabolic task analysis was performed in MATLAB using the Human1 genome-scale metabolic model for an in-depth analysis of the metabolic profiles of the seven T cell types.

Results: While the core functions of elevated genes were immune-related processes, the seven T cell types also displayed varying levels of specialization. In Treg cells, cell division processes were elevated, and γδ T cells performed a range of innate immune responses not elevated in the other T cell types. In most of the metabolic tasks and pathways studied, Treg cells and MAIT cells had the highest activity and naïve T cells the lowest. Against expectations, only small differences between the T cell types were observed in carbon metabolism. Significant differences were found in reactions associated with lipid, amino acid and nucleotide metabolism.

Conclusion: By integrating various computational methods in a reproducible workflow, this study showcased cell-type specific immunological functions and metabolic pathways of seven T cell types, followed by an exploration of metabolic tasks critical for T cell metabolism and function.