Hypoxia-inducible factors regulate T cell metabolism and function

Abstract

Resolution of infection requires the coordinated response of heterogeneous cell types to a range of physiological and pathological signals to regulate their proliferation, migration, differentiation, and effector functions. One mechanism by which immune cells integrate these signals is through modulating metabolic activity. A well-studied regulator of cellular metabolism is the hypoxia-inducible factor (HIF) family, the highly conserved central regulators of adaptation to limiting oxygen tension. HIFs regulation of cellular metabolism and a variety of effector, signaling, and trafficking molecules has made these transcription factors a recent topic of interest in T cell biology. Low oxygen availability, or hypoxia, increases expression and stabilization of HIF in immune cells, activating molecular programs both unique and common among cell types, including glycolytic metabolism. Notably, numerous oxygen-independent signals, many of which are active in T cells, also result in enhanced HIF activity. Here, we discuss both oxygen-dependent and -independent regulation of HIF activity in T cells and the resulting impacts on metabolism, differentiation, function and immunity.

Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia

“…S1G). HIF1α expression is usually associated with hypoxia, but T cells also upregulate HIF1α upon activation (14), so we believe the trend towards increased HIF1α in metformin-treated TIL may be a readout of increased T-cell activation (Fig. 3D and Supplementary Fig.…”

Constitutive Glycolytic Metabolism Supports CD8+ T Cell Effector Memory Differentiation during Viral Infection

“…Our studies and those of others highlight the difficulty and importance of discerning direct impacts of manipulating cellular metabolism in vivo through modulation of critical cellular sensors such as HIF (Doedens et al, 2013; Finlay et al, 2012; Shi et al, 2011), mTOR (Araki et al, 2009; Lee et al, 2010; Rao et al, 2010; Shrestha et al, 2014), and AMPK (Blagih et al, 2015; Pearce et al, 2009; Rolf et al, 2013). For example, in our model conditional deletion of Vhl constitutively stabilizes HIF, results in the upregulation of numerous transcriptional targets, some that promote glycolytic metabolism, and some that may promote memory CD8 + T cell differentiation independent of cellular metabolism (Kim et al, 2006; Phan and Goldrath, 2015). These results further emphasize the need for future studies dissecting whether transcriptional or metabolic requirements are paramount in specifying T cell fate.…”

“…The HIF family of transcription factors (HIFs) serves as the central sensor of oxygen tension and adaptation to low oxygen tensions in all cells, including T cells (Haase et al, 2001; McNamee et al, 2013; Nizet and Johnson, 2009; Phan and Goldrath, 2015). Post-translational regulation by the von Hippel Lindau tumor suppressor protein (VHL), an E3 ubiquitin ligase, drives degradation of HIFα subunits in normal oxygen tensions (McNamee et al, 2013; Nizet and Johnson, 2009; Phan and Goldrath, 2015). HIF drives oxygen conservation through the upregulation of glycolytic metabolism and direct suppression of oxygen consumption by mitochondria (Nizet and Johnson, 2009).…”

“…Suppression of oxygen consuming mitochondrial respiration is the result of HIF-dependent increased expression of nearly all glycolytic enzymes. In particular, HIF drives expression of lactate dehydrogenase a (LDHA), which potentiates increased glycolytic throughput, and simultaneously suppresses mitochondrial respiration by preventing the shunting of pyruvate into the citric acid cycle through inhibition of pyruvate dehydrogenase by also increasing expression of pyruvate dehydrogenase kinase 1 (PDK1) (Kim et al, 2006; Phan and Goldrath, 2015). Thus, HIF-dependent enhancement of glycolytic metabolism and suppression of cellular respiration presents a unique model by which to interrogate the relationship between metabolic pathway choice and CD8 + T cell differentiation.…”

Role of the Hypoxia-Inducible Factor in Periodontal Inflammation

“…Activation of HIF also upregulates the expression of pyruvate dehydrogenase kinase, which reduces the incorporation of pyruvate into the citric acid cycle [24]. This metabolic switch is essential for the hosts' defense because such HIF-1α-regulated glycolytic metabolism is required in B cell development [25] and T cell metabolism [26].…”