Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation
TL;DR: It is shown that the intracellular supply of large neutral amino acids in T cells was regulated by pathogens and the T cell antigen receptor (TCR), and that Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation.
Abstract: T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L ('leucine-preferring system') transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation. The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Control of expression of the System L transporter by pathogens is thus a critical metabolic checkpoint for T cells.
Citations
More filters
TL;DR: A perspective on the roles of class I PI3Ks in the regulation of cellular metabolism and in immune system functions is provided, two topics closely intertwined with cancer biology.
1,461 citations
Cites background from "Control of amino-acid transport by ..."
...Similarly, in activated CD8 T cells, leucine uptake via the system L amino acid transporter Slc7a5 is required for mTORC1 activity, c-Myc translation, and metabolic reprogramming (Sinclair et al., 2013), whereas PI3K/AKT signaling is dispensable for these outcomes...
[...]
...…in activated CD8+ T cells, leucine uptake via the system L amino acid transporter Slc7a5 is required for mTORC1 activity, c-Myc translation, and metabolic reprogramming (Sinclair et al., 2013), whereas PI3K/AKT signaling is dispensable for these outcomes Cell 170, August 10, 2017 615 Figure 5....
[...]
TL;DR: It is becoming increasingly clear that T cell function is intimately linked to metabolic programs, and as such there is a considerable and growing interest in developing techniques that target metabolism for immunotherapy.
Abstract: Background Naive lymphocytes circulate in the body in a resting state, but upon recognition of foreign antigen and receipt of proper costimulatory signals, these cells become activated, undergo a rapid burst in proliferation, and assume effector functions aimed at controlling or killing the invader. There is a growing appreciation that changes in peripheral T cell function are not only supported by but are dependent on metabolic reprogramming and that specific effector functions cannot proceed without adopting the correct metabolism. However, the reasons underlying why T cells adopt specific metabolic programs and the impact that these programs have on T cell function and, ultimately, immunological outcome remain unclear. T cell function and fate are dependent on metabolic reprogramming. As T cells differentiate during an immune response, they move from what are presumably nutrient-replete lymphoid organs to sites of cancer or infection, where oxygen, nutrients, growth factors, and other signals may become limiting. These metabolically restrictive environments force T cells to metabolically adapt in order to survive and perform their necessary functions. Advances Research into the metabolism of tumor cells has provided valuable insight into the metabolic pathways important for cell proliferation and survival, as well as the influence of metabolites themselves on signal transduction and epigenetic programming. Many of these concepts have shaped how we view metabolism in T cells. However, it is important to note that, unlike tumors, T cells rapidly transition between resting catabolic states (naive and memory T cells) to one of growth and proliferation (effector T cells) as part of a normal developmental program. In addition, as T cells differentiate during an immune response they also move from what are presumably nutrient-replete lymphoid organs to sites of cancer or infection, where oxygen, nutrients, and growth factors may become limiting. Thus, T cells must metabolically adapt to these changing conditions in order to perform their necessary functions. In this review, we highlight emerging areas in the metabolism of these dynamic cells and discuss the potential impact of metabolic control on T cell fate, plasticity, and effector function. Outlook It is becoming increasingly clear that T cell function is intimately linked to metabolic programs, and as such there is a considerable and growing interest in developing techniques that target metabolism for immunotherapy. Studying metabolism has often been difficult for the nonexpert, because many of the experimental approaches require specialized instrumentation that has not been widely available. Furthermore, acquiring sufficient cellular material for ex vivo analyses, coupled with the inherent difficulty of assessing cellular metabolism in vivo during an immune response, presents substantial challenges to scientists studying the metabolism of immune cells. Nevertheless, understanding how environmental cues and cellular metabolism influence the outcome of T cell–mediated immune responses will be critical for learning how to exploit metabolism to alter disease outcome. Overall, we are just beginning to understand the pathways that regulate metabolism in lymphocytes and how T cells adapt to changes in their microenvironment, particularly in vivo; this area of immunology is poised for substantial advances in the years to come.
1,022 citations
Cites background from "Control of amino-acid transport by ..."
...Recently, it was found that engagement of the TCR leads to the expression of Slc7a5, an amino acid transporter that mediates the import of large neutral amino acids, such as leucine (8)....
[...]
TL;DR: Elevating L-arginine levels induced global metabolic changes including a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the generation of central memory-like cells endowed with higher survival capacity and, in a mouse model, anti-tumor activity.
938 citations
Cites background from "Control of amino-acid transport by ..."
...…(OXPHOS) for their energy supply, activated T cells consume large amounts of glucose, amino acids, and fatty acids and adjust their metabolic pathways toward increased glycolytic and glutaminolytic activity (Blagih et al., 2015; Rolf et al., 2013; Sinclair et al., 2013; Wang et al., 2011)....
[...]
TL;DR: The role of lymphocyte metabolism on immune cell development and function and the importance of “goodtenance” in immune cell function is discussed.
Abstract: Lymphocytes must adapt to a wide array of environmental stressors as part of their normal development, during which they undergo a dramatic metabolic remodeling process. Research in this area has yielded surprising findings on the roles of diverse metabolic pathways and metabolites, which have been found to regulate lymphocyte signaling and influence differentiation, function and fate. In this review, we integrate the latest findings in the field to provide an up-to-date resource on lymphocyte metabolism.
847 citations
TL;DR: This review of immunometabolism will reference the most recent literature to cover the choices that environments impose on the metabolism and function of immune cells and highlight their consequences during homeostasis and disease.
787 citations
Cites background from "Control of amino-acid transport by ..."
...Glutamine controls mTOR activation in T cells and macrophages and is also a key substrate for protein O-GlcNAcylation and synthesis of S-2HG that regulate effector T cell function and differentiation (Sinclair et al., 2013; Swamy et al., 2016; Tyrakis et al., 2016)....
[...]
References
More filters
TL;DR: Metabolic tracer analysis revealed a Myc-dependent metabolic pathway linking glutaminolysis to the biosynthesis of polyamines, which may represent a general mechanism for metabolic reprogramming under patho-physiological conditions.
1,632 citations
TL;DR: It is shown that cellular uptake of L-glutamine and its subsequent rapid efflux in the presence of essential amino acids (EAA) is the rate-limiting step that activates mTOR.
1,540 citations
TL;DR: The Immunological Genome Project combines immunology and computational biology laboratories in an effort to establish a complete 'road map' of gene-expression and regulatory networks in all immune cells.
Abstract: nology is an ideal field for the application of systems approaches, with its detailed descriptions of cell types (over 200 immune cell types are defined in the scope of the Immunological Genome Project (ImmGen)), wealth of reagents and easy access to cells. Thanks to the broad and robust approaches allowed by gene-expression microarrays and related techniques, the transcriptome is probably the only ‘-ome’ that can be reliably tackled in its entirety. Generating a complete perspective of gene expression in the immune system
1,497 citations
TL;DR: It is shown that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what was expected, the immunosuppressive drug Rapamycin has immunostimulatory effects on the generation of memoryCD8 T cells.
Abstract: Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Here we show that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase (effector to memory transition) it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.
1,384 citations
TL;DR: HIF1α induction by mTOR represents a metabolic checkpoint for the differentiation of TH17 and Treg cells and is associated with good progenitor cell status in mice.
Abstract: Upon antigen stimulation, the bioenergetic demands of T cells increase dramatically over the resting state. Although a role for the metabolic switch to glycolysis has been suggested to support increased anabolic activities and facilitate T cell growth and proliferation, whether cellular metabolism controls T cell lineage choices remains poorly understood. We report that the glycolytic pathway is actively regulated during the differentiation of inflammatory T H 17 and Foxp3-expressing regulatory T cells (T reg cells) and controls cell fate determination. T H 17 but not T reg cell–inducing conditions resulted in strong up-regulation of the glycolytic activity and induction of glycolytic enzymes. Blocking glycolysis inhibited T H 17 development while promoting T reg cell generation. Moreover, the transcription factor hypoxia-inducible factor 1α (HIF1α) was selectively expressed in T H 17 cells and its induction required signaling through mTOR, a central regulator of cellular metabolism. HIF1α–dependent transcriptional program was important for mediating glycolytic activity, thereby contributing to the lineage choices between T H 17 and T reg cells. Lack of HIF1α resulted in diminished T H 17 development but enhanced T reg cell differentiation and protected mice from autoimmune neuroinflammation. Our studies demonstrate that HIF1α–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T H 17 and T reg cells.
1,377 citations