Fueling Immunity: Insights into Metabolism and Lymphocyte Function

By Erika L. Pearce, M. Poffenberger, Chih-Hao Chang, Russell G. Jones. Science, 2013

1,290 citations recorded by the source corpus.

Background Naïve 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 (naïve 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. Lymphocyte Metabolism Lymphocytes are highly dynamic cells, undergoing extensive proliferation upon infection and then reducing in number upon pathogen clearance. Lymphocytes also circulate through many different tissue environments that vary in their nutrient and oxygen availability. Recent studies have revealed changes in metabolic programming that facilitate this dynamic behavior. How these changes occur and the specific effects that they have on lymphocyte function and on the ultimate outcome of an infection are not well understood. Pearce et al. (1242454) review recent progress in this area, suggest how parallels might be found in studying the metabolic changes seen in tumor cells, and propose challenges for the future. Lymphocytes face major metabolic challenges upon activation. They must meet the bioenergetic and biosynthetic demands of increased cell proliferation and also adapt to changing environmental conditions, in which nutrients and oxygen may be limiting. An emerging theme in immunology is that metabolic reprogramming and lymphocyte activation are intricately linked. However, why T cells adopt specific metabolic programs and the impact that these programs have on T cell function and, ultimately, immunological outcome remain unclear. Research on tumor cell metabolism has provided valuable insight into metabolic pathways important for cell proliferation and the influence of metabolites themselves on signal transduction and epigenetic programming. In this Review, we highlight emerging concepts regarding metabolic reprogramming in proliferating cells and discuss their potential impact on T cell fate and function.

Subfields: Cancer Research, Immunology

View Paper: https://www.semanticscholar.org/paper/518aa5b26772d6dcd1b09005f3af65a0ea6116c3

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Citations in the corpus

Memory CD8+ T cells use cell intrinsic lipolysis to support the metabolic programming necessary for development (2014, background): “, 2013), memory T cells rely on this metabolic pathway, and in particular, the use of fatty acids (FA) to fuel this process (Pearce et al., 2013).”
L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity (2016, background): “Metabolic activity is also critical to determine T cell fate and memory formation (MacIver et al., 2013; Pearce et al., 2013; Wang and Green, 2012).”
Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019, background): “mTOR plays an important role in T cell activation and differentiation, especially of naïve CD4 T cells in their differentiation toward Th1 or Th17 phenotypes (201, 202).”
Mitochondria in the regulation of innate and adaptive immunity (2015, positive): “…signaling pathways often include detours that transmit through metabolic machinery to ensure cooperation of metabolism in the cell-fate decision (Pearce et al., 2013) It is becoming clear that cellular metabolism plays a highly active role in determining cellular destiny in the immune system—in…”
mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity (2014, background): “mTOR acts as a sensor of the metabolic environment (21) and functions as amaster regulator of glucose metabolism in activated lymphocytes (22).”
Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity (2016, background): “These circuits have important functional consequences based on how cells use metabolic substrates: for example, type 1 inflammatory macrophages (M[IFNg]) rely on increased glycolysis (Mills and O’Neill, 2015; Pearce et al., 2013; Tan et al., 2015), whereas tolerantmacrophages (M[IL-4]) rely on oxida”
Metabolic competition in the tumor microenvironment is a driver of cancer progression (2015, background): “We (Chang et al., 2013; O’Sullivan and Pearce, 2015; Pearce et al., 2013), and others (Mellor and Munn, 2008; Mockler et al.”
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. (2019, background): “Tumor growth is typically supported by aerobic glycolysis, the same metabolic lifestyle used by efficient Teff cells (100, 113, 114).”
Metabolic Instruction of Immunity (2017, neutral): “The central concepts of immune cell metabolism have been covered extensively in several reviews (Buck et al., 2015; MacIver et al., 2013; O’Neill and Pearce, 2016; O’Neill et al., 2016; Pearce et al., 2013), and thus will not be discussed at length here.”
T cell metabolism drives immunity (2015, background): “Although aerobic glycolysis is less efficient than OXPHOS at yielding an abundance of ATP per molecule of glucose, aerobic glycolysis can generate metabolic intermediates important for cell growth and proliferation, and provides a way to maintain redox balance (NAD+/NADH) in the cell (Fig.”