mTOR and lymphocyte metabolism

Highlights

• Different T cell activation states have distinct metabolic profiles and mTOR activity.

• mTOR orchestrates T cell quiescence, functional activation, and fate decisions.

• mTOR is activated by and impinge upon antigen receptor and other immune signaling.

• mTOR senses metabolic cues and coordinates T cell metabolic reprogramming.

Upon antigen engagement and proper co-stimulation, naïve lymphocytes exit quiescence and undergo clonal expansion and differentiate into functional effector cells, after which they either die through apoptosis or survive as memory cells. Lymphocytes at different activation stages exhibit distinct metabolic signatures. Emerging evidence highlights a central role for the mechanistic target of rapamycin (mTOR) in bridging immune signals and metabolic cues to direct lymphocyte proliferation, differentiation and survival. Here we review recent advances in understanding the functional significance and signal transduction of mTOR in T cell biology, and the interplay between mTOR signaling and metabolic programs.

Introduction

Mammalian cells are usually exposed to a constant supply of nutrients, but they do not normally take up nutrients and proliferate until they are stimulated by extrinsic factors [1]. Naïve lymphocytes, like most cells in normal tissues, have a quiescent status, in which they primarily rely on catabolic metabolism and derive most of their ATP from oxidative phosphorylation, particularly fatty acid β-oxidation [2, 3, 4••]. Quiescent lymphocytes also break down intracellular components through autophagy to supply molecules for oxidative phosphorylation [5]. Upon antigen recognition and co-stimulation, lymphocytes downregulate fatty acid β-oxidation and rapidly increase glycolytic, glutaminolytic and pentose phosphate pathways to provide biosynthetic materials and energy for cell growth and proliferation [3, 4••, 6]. Activated and effector T cells preferentially utilize aerobic glycolysis to meet their energy demands, a phenomenon known as the Warburg effect, which is also a metabolic feature of many cancer cells [1]. After clonal expansion and clearance of invading foreign pathogens, most effector T cells undergo apoptosis while some differentiate into long-lived memory cells. Memory T cells, like naïve T cells, are quiescent and have a catabolic metabolism [7, 8]. A separate T cell subset, FOXP3⁺ regulatory T cells (T_reg), also exhibits relatively high fatty acid β-oxidation but low glycolysis [9••, 10]. Thus, during immune responses, T cells experience two major metabolic switches, from catabolic naïve T cells to anabolic activated/effector T cells and then again transition into catabolic memory T cells (Figure 1). Emerging evidence indicates that metabolism is closely coupled with the differentiation and function of T cells at different stages of their life span [11].

The serine/threonine kinase mTOR consists of two distinct complexes: mTOR complex 1 (mTORC1) and 2 (mTORC2). Two scaffold proteins, regulatory associated protein of mTOR (RAPTOR) and rapamycin-insensitive companion of mTOR (RICTOR), are the defining components of mTORC1 and mTORC2, respectively [12]. While mTORC1 is sensitive to rapamycin, mTORC2 can be inhibited by prolonged or high dose of rapamycin treatment in CD4⁺ T cells [13••, 14••], but not in effector CD8⁺ T cells [15^•]. Many upstream signals activate mTORC1 pathway through the small GTPase RHEB (RAS homologue enriched in brain). The tuberous sclerosis 1 (TSC1) and TSC2 form a complex that inactivates RHEB through its GAP (GTPase-activating protein) activity, thereby suppressing mTORC1 activity. Further upstream, the PI3K-AKT pathway inactivates TSC1/TSC2 complex while AMP-activated protein kinase (AMPK) enhances its activity. Therefore, TSC1/TSC2 complex functions as a molecular switch that controls mTORC1 activity. S6K1 and 4E-BP1 are two best-characterized downstream targets of mTORC1 that regulates protein translation. Moreover, mTORC1 pathway also promotes glycolysis and lipid biosynthesis while inhibiting autophagy. mTORC2 is activated by PI3K signaling, but detailed mechanism is lacking. mTORC2 controls several AGC family kinases, including AKT, SGK1 and PKC-α and is involved in regulating metabolism, apoptosis and cytoskeletal organization [12]. In particular, phosphorylation of AKT-Ser473 by mTORC2 promotes FOXO1/3a phosphorylation and subsequent cytoplasm translocation and degradation [16, 17].

In lymphocytes, diverse environmental signals, including antigens, growth factors, cytokines and nutrients regulate mTOR to direct immune responses and fate decisions [18, 19]. Since the roles of mTOR and metabolic pathways have been extensively studied in mature T cells in the periphery, we will mainly focus on these cells. First, we will briefly describe the roles of mTOR in T cell homeostasis under steady state and antigen-triggered activation and differentiation. Second, we will discuss the functional effects and mechanistic basis of mTOR in sensing and propagating diverse immune signals, especially those mediated by TCR, co-stimulation and cytokine receptors. Third, we will present the emerging evidence on mTOR-dependent metabolic reprogramming of T cell responses, by focusing on the interaction between mTOR and transcription factors associated with cell metabolism such as MYC and HIF1, and the potential interplay between mTOR-controlled metabolites and immune signaling. As our discussion focuses on T cells, we refer the readers to an excellent recent review describing the PI3K-AKT-mTOR pathway in B cells [20].