The Energy Sensor AMPK Regulates T Cell Metabolic Adaptation and Effector Responses In Vivo

Abstract

Naive T cells undergo metabolic reprogramming to support the increased energetic and biosynthetic demands of effector T cell function. However, how nutrient availability influences T cell metabolism and function remains poorly understood. Here we report plasticity in effector T cell metabolism in response to changing nutrient availability. Activated T cells were found to possess a glucose-sensitive metabolic checkpoint controlled by the energy sensor AMP-activated protein kinase (AMPK) that regulated mRNA translation and glutamine-dependent mitochondrial metabolism to maintain T cell bioenergetics and viability. T cells lacking AMPKα1 displayed reduced mitochondrial bioenergetics and cellular ATP in response to glucose limitation in vitro or pathogenic challenge in vivo. Finally, we demonstrated that AMPKα1 is essential for T helper 1 (Th1) and Th17 cell development and primary T cell responses to viral and bacterial infections in vivo. Our data highlight AMPK-dependent regulation of metabolic homeostasis as a key regulator of T cell-mediated adaptive immunity.

The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions

“…Glucose metabolism did not markedly contribute to ATP maintenance in naive or EM CD4 + T cells under normoxia. This is consistent with previous reports (20,21) and consistent with the fact that T cells have the capacity to use both fatty acid oxidation and glutaminolysis to provide tricarboxylic acid cycle substrates and thereby maintain cellular bioenergetics (12,21). After 4-8 h of hypoxia, glucose metabolism did significantly contribute to ATP sufficiency-intriguingly, however, to a similar extent in both naive and EM CD4 + T cells despite the increased glycolytic reserve of EM CD4 + T cells.…”

“…This did not markedly impact ATP generation in normoxic naive or EM CD4 + T cells (Fig. 3B), consistent with previous reports (20,21). Furthermore, also after 4 h of hypoxia there was no significant reduction of the cellular ATP pool in either T cell subset (Fig.…”

Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

“…Adenosine monophosphate-activated protein kinase (AMPK) regulates cellular energy levels, T-cell differentiation and development of memory. 132 AMPK is activated by metformin, a type-2 diabetes drug, 133 that reduces bacterial burden and ameliorates lung pathology in mice and humans by enhancing autophagy and increasing ROS production. 92 Metformin adjunctive treatment however failed to improve sterilizing activity and TB relapsed in mice, with no significant effect being reported for culture conversion rates in diabetes mellitus patients with TB.…”

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…AMPK shuts down energy-consuming processes such as protein, cholesterol and fatty acid synthesis, while promoting energy-generating processes such as glucose import and fatty acid oxidation 92 . AMPK blocks protein translation by inhibiting mTORC1, and the deletion of LKB1 or AMPK in T cells promotes the translation of inflammatory cytokines, even under conditions of low energy availability 107,108 . AMPK deficiency also releases mTORC1 to activate HIF1α and promote the expression of genes that favour glyco lysis 109 , and aero bic glycolysis itself promotes the production of inflammatory cytokines 110 .…”