Metabolism in T cell activation and differentiation

When naïve or memory T cells encounter foreign antigen along with proper co-stimulation they undergo rapid and extensive clonal expansion. In mammals, this type of proliferation is fairly unique to cells of the adaptive immune system and requires a considerable expenditure of energy and cellular resources. While research has often focused on the roles of cytokines, antigenic signals, and co-stimulation in guiding T cell responses, data indicate that, at a fundamental level, it is cellular metabolism that regulates T cell function and differentiation and therefore influences the final outcome of the adaptive immune response. This review will focus on some earlier fundamental observations regarding T cell bioenergetics and its role in regulating cellular function, as well as recent work that suggests that manipulating the immune response by targeting lymphocyte metabolism could prove useful in treatments against infection and cancer.

Introduction

Unlike the case for unicellular organisms where dramatic changes in nutrient availability affect proliferation, mammalian cells reside in nutrient-rich environments where cellular proliferation is controlled by extrinsic signals, such as growth factors, which regulate nutrient utilization [1]. One of the most striking changes to affect T cells after initial antigenic stimulation is an increase in cell size accompanied by a metabolic switch to glycolysis, which is required to support their growth, proliferation, and effector functions [2, 3, 4] (Figure 1). During TCR stimulation, signals from growth factor cytokines like IL-2, and the ligation of co-stimulatory CD28, lead to an increase in glycolysis by inducing the PI3K-dependent activation of Akt [5, 6]. Activated Akt can promote the mTOR (mammalian target of rapamycin) pathway, a key regulator of translation [7], as well as stimulate glycolysis by increasing glycolytic enzyme activity and enhancing the expression of nutrient transporters, enabling increased utilization of glucose and amino acids [8, 9, 10••, 11, 12, 13]. Together these changes lead to the increase in nutrient utilization and glucose metabolism that facilitates activation and proliferation.

As T cells undergo clonal expansion they preferentially ferment glucose to meet their energy demands, even though there is sufficient oxygen present to support mitochondrial oxidative phosphorylation [14, 15, 16]. This phenomenon is known as the Warburg effect [17], and is an unusual metabolic aspect of proliferating T cells and cancer cells. Since ATP production by aerobic glycolysis is much less efficient than by oxidative phosphorylation, a question remains as to why proliferating T cells favor this form of metabolism. One explanation, largely based on observations from Craig Thompson's laboratory, is that glycolysis is an essentially anabolic form of metabolism that leaves cellular building blocks, such as amino acids and fatty acids untouched, as well as produces lactate, all of which can be incorporated into cellular components [18]. A cell that converts building blocks into biomass most efficiently will proliferate the fastest and in a host fighting an infection, rapid expansion of antigen-specific T cells could offer a decisive advantage [19].

In contrast to proliferating T cells, quiescent T cells (i.e. naïve and memory cells), like most cells in normal tissues, interchangeably breakdown glucose, amino acids, and lipids to catabolically fuel ATP generation [2, 18] (Figure 1). The posited effects of growth factors on resting T cell survival are related to their ability to modulate the surface expression of nutrient transporters [20]. Quiescent cells can also use autophagy (the break down of intracellular components) to supply the molecules to fuel oxidative phosphorylation [21]. There is growing evidence that quiescence is under active transcriptional control [22]. TOB1 (transducer of ERBB2 1) [23], LKLF (lung Krüppel-like factor) [24], and FOXO (Forkhead box class O) transcription factors all have been suggested to promote quiescence in lymphocytes by actively maintaining the expression of inhibitors of cellular activation [25, 26]. Furthermore, FOXO transcription factors have been shown to modulate metabolic functions [27, 28] and the family of Krüppel-like factors (KLFs) has been shown to regulate adipocyte differentiation and glucose homeostasis in mammals [29], which may suggest a degree of metabolic control in maintaining quiescence.

Implicit in the striking divergence of metabolic phenotypes between proliferating and quiescent T cells is the idea that the conversion, or switching, between differing metabolic states is required to effectively generate a given T cell fate [10••, 18]. This not only applies to the switch from quiescence to glycolysis that accompanies naïve T cell activation, but also to the promotion of catabolism that appears to be important for the generation of quiescent memory T cells after infection [30^••] (Figure 2). Each of these metabolic states represents a unique target of intervention for manipulating the T cell response and ameliorating disease.