Mouse lung Tissue Resident Memory (TRM) CD8 T cell subsets have distinct metabolic profiles from each other and from non-TRM

Abstract

AbstractTissue resident memory CD8 T cells (TRM) principally reside in peripheral non-lymphoid tissues and confer protection against a variety of illnesses ranging from infections to cancers. The functions of different CD8 T cell subsets in the skin have been linked with distinct metabolic pathways and differ from other CD8 T cell subsets. For example, they undergo fatty acid oxidation and oxidative phosphorylation to a greater degree than circulating memory and naïve cells. However, it is unclear if this programming is universal. Our work demonstrates TRM are not homogenous and, based on integrin expression, exist as subsets with distinct gene expression and function. We hypothesize that lung TRM with different integrin profiles will utilize unique metabolic programs. First, differential expression and pathway analysis was conducted on RNAseq datasets yielding important differences between subsets. Next, metabolic models were constructed and interrogated. Functional metabolite uptake assays were conducted, and the levels of oxidative phosphorylation, mitochondrial mass, and neutral lipids were measured. Furthermore, T cell differentiation studies were conducted varying concentrations of metabolites to investigate the causal relationship in TRM development, demonstrating that, in vitro, lipid conditions impact memory cell maintenance generally, and that glucose concentration impacts TRM-like differentiation specifically, with no effect on central memory-like T cell differentiation. In summary, a diverse set of analyses were utilized to demonstrate lung TRM have unique metabolic profiles and that metabolic microenvironments alter differentiation in vitro.