Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8⁺ T cells

Abstract

We recently reported that differentiation of CD8 1 T cells from the naïve to the effector state involves the upregulation of glucose-dependent metabolism. Glucose deprivation or inhibition of glycolysis by 2-deoxy-D-glucose (2-DG) selectively inhibited production of IFN-g but not of IL-2. To determine a more global role of glucose metabolism on effector T-cell function, we performed gene array analysis on CD8 1 effector T cells stimulated in the presence or absence of 2-DG. We observed that expression of only 10% of genes induced by TCR/CD28 signaling was inhibited by 2-DG. Among these were genes for key cytokines, cell cycle molecules, and cytotoxic granule proteins. Consistent with these results, production of IFN-g and GM-CSF, cell cycle progression, upregulation of cyclin D2 protein, cytolytic activity, and upregulation of granzyme B protein and also conjugate formation were exquisitely glucose-dependent. In contrast to glucose, oxygen was little utilized by CD8 1 effector T cells, and relative oxygen deprivation did not inhibit these CTL functional properties. Our results indicate a particularly critical role for glucose in regulating specific effector functions of CD8 1 T cells and have implications for the maintenance of the effector phase of cellular immune responses in target tissue microenvironments such as a solid tumor.

TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis

“…To maintain their housekeeping functions T cells produce ATP mainly through catabolic processes that breakdown amino acids, glucose and lipids via OXPHOS (37,38). Upon Ag-specific activation, however, T cells undergo an immediate glycolytic switch to meet the energy demands for proliferation and for optimal effector function (46,47,59). Amino acids and lipids are then used for the production of molecules required to respond to infectious agents, and the generation of ATP is progressively more dependent on aerobic glycolysis (60,61).…”

“…Taken together, these data indicate that T cells can choose which metabolic process (aerobic glycolysis versus mitochondrial respiration) to use to produce the required energy, depending on the availability of nutrients. T cell activation through TLR requires mitochondrial respiration, but not glucose, to fuel IFN-g production Previous studies have found that effector CD8 + T cells rely on glucose metabolism for optimal production of IFN-g (45)(46)(47). In this study, we asked whether TLR-mediated IFN-g production also depends on glucose availability.…”

Th1/Th17 Plasticity Is a Marker of Advanced β Cell Autoimmunity and Impaired Glucose Tolerance in Humans

“…+ T cells has been shown to be glucosedependent (31)(32)(33). The HbA1c values and fasting glucose concentrations were, however, in the normal range in most of the children with advanced b cell autoimmunity.…”

Immune Gene and Cell Enrichment Is Associated with a Good Prognosis in Ependymoma

“…Only phosphorylase kinase, ␥-1 (PHKG1) had no documented evidence of immune involvement, with its known function being as a key glycogenolytic enzyme. However, the dependence of T-lymphocyte activity on glucose metabolism suggests a potential role in immune function for this gene (29). In the reverse analysis of genes that overlapped between both bad prognosis groups, that is, the recurrent EPN phenotype and TTP negative correlates, only two genes were identified: programmed cell death-6 (PDCD6) and opsin-3 (OPN3), which are known to have roles in TCR-induced apoptosis and photoreception, respectively.…”