Exhausted CD8 T (Tex) cells are a distinct cell lineage that arise during chronic infections and cancers in animal models and humans. Tex cells are characterized by progressive loss of effector fun...

https://www.annualreviews.org/doi/pdf/10.1146/annurev-immunol-041015-055318

CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer

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.

/pdf/fueling-immunity-insights-into-metabolism-and-lymphocyte-4g2xg6h8bj.pdf

Fueling immunity: insights into metabolism and lymphocyte function.

T cell activation leads to dramatic shifts in cell metabolism to protect against pathogens and to orchestrate the action of other immune cells. Quiescent T cells require predominantly ATP-generating processes, whereas proliferating effector T cells require high metabolic flux through growth-promoting pathways. Further, functionally distinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. Pathways that control immune cell function and metabolism are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell functions. As a result of these findings, cell metabolism is now appreciated as a key regulator of T cell function specification and fate. This review discusses the role of cellular metabolism in T cell development, activation, differentiation, and function to highlight the clinical relevance and opportunities for therapeutic interventions that may be used to disrupt immune pathogenesis.

/pdf/metabolic-regulation-of-t-lymphocytes-56bbc2ulv0.pdf

Metabolic regulation of T lymphocytes.

Metabolic changes in cells that participate in inflammation, such as activated macrophages and T-helper 17 cells, include a shift towards enhanced glucose uptake, glycolysis and increased activity of the pentose phosphate pathway. Opposing roles in these changes for hypoxia-inducible factor 1α and AMP-activated protein kinase have been proposed. By contrast, anti-inflammatory cells, such as M2 macrophages, regulatory T cells and quiescent memory T cells, have lower glycolytic rates and higher levels of oxidative metabolism. Some anti-inflammatory agents might act by inducing, through activation of AMP-activated protein kinase, a state akin to pseudo-starvation. Altered metabolism may thus participate in the signal-directed programs that promote or inhibit inflammation.

/pdf/metabolism-of-inflammation-limited-by-ampk-and-pseudo-3wapkuw986.pdf

Metabolism of inflammation limited by AMPK and pseudo-starvation

The linkage of individuals with obesity and COVID-19 is controversial and lacks systematic reviews. After a systematic search of the Chinese and English language literature on COVID-19, 75 studies were used to conduct a series of meta-analyses on the relationship of individuals with obesity-COVID-19 over the full spectrum from risk to mortality. A systematic review of the mechanistic pathways for COVID-19 and individuals with obesity is presented. Pooled analysis show individuals with obesity were more at risk for COVID-19 positive, >46.0% higher (OR = 1.46; 95% CI, 1.30-1.65; p < 0.0001); for hospitalization, 113% higher (OR = 2.13; 95% CI, 1.74-2.60; p < 0.0001); for ICU admission, 74% higher (OR = 1.74; 95% CI, 1.46-2.08); and for mortality, 48% increase in deaths (OR = 1.48; 95% CI, 1.22-1.80; p < 0.001). Mechanistic pathways for individuals with obesity are presented in depth for factors linked with COVID-19 risk, severity and their potential for diminished therapeutic and prophylactic treatments among these individuals. Individuals with obesity are linked with large significant increases in morbidity and mortality from COVID-19. There are many mechanisms that jointly explain this impact. A major concern is that vaccines will be less effective for the individuals with obesity.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/obr.13128

Individuals with obesity and COVID-19: A global perspective on the epidemiology and biological relationships.

T cell activation leads to engagement of cellular metabolic pathways necessary to support cell proliferation and function. However, our understanding of the signal transduction pathways that regulate metabolism and their impact on T cell function remains limited. The liver kinase B1 (LKB1) is a serine/threonine kinase that links cellular metabolism with cell growth and proliferation. In this study, we demonstrate that LKB1 is a critical regulator of T cell development, viability, activation, and metabolism. T cell-specific ablation of the gene that encodes LKB1 resulted in blocked thymocyte development and a reduction in peripheral T cells. LKB1-deficient T cells exhibited defects in cell proliferation and viability and altered glycolytic and lipid metabolism. Interestingly, loss of LKB1 promoted increased T cell activation and inflammatory cytokine production by both CD4(+) and CD8(+) T cells. Activation of the AMP-activated protein kinase (AMPK) was decreased in LKB1-deficient T cells. AMPK was found to mediate a subset of LKB1 functions in T lymphocytes, as mice lacking the α1 subunit of AMPK displayed similar defects in T cell activation, metabolism, and inflammatory cytokine production, but normal T cell development and peripheral T cell homeostasis. LKB1- and AMPKα1-deficient T cells each displayed elevated mammalian target of rapamycin complex 1 signaling and IFN-γ production that could be reversed by rapamycin treatment. Our data highlight a central role for LKB1 in T cell activation, viability, and metabolism and suggest that LKB1-AMPK signaling negatively regulates T cell effector function through regulation of mammalian target of rapamycin activity.

The Liver Kinase B1 Is a Central Regulator of T Cell Development, Activation, and Metabolism

/pdf/activation-to-link-nutrition-and-immunity-leptin-x9yhclf1fx.pdf

Activation To Link Nutrition and Immunity Leptin Metabolically Licenses T Cells for

Cell Development, Activation, and Metabolism The Liver Kinase B1 Is a Central Regulator of T

Immune responses are highly energy-dependent processes. Activated T cells increase glucose uptake and aerobic glycolysis to survive and function. Malnutrition and starvation limit nutrients and are associated with immune deficiency and increased susceptibility to infection. Although it is clear that immunity is suppressed in times of nutrient stress, mechanisms that link systemic nutrition to T cell function are poorly understood. We show in this study that fasting leads to persistent defects in T cell activation and metabolism, as T cells from fasted animals had low glucose uptake and decreased ability to produce inflammatory cytokines, even when stimulated in nutrient-rich media. To explore the mechanism of this long-lasting T cell metabolic defect, we examined leptin, an adipokine reduced in fasting that regulates systemic metabolism and promotes effector T cell function. We show that leptin is essential for activated T cells to upregulate glucose uptake and metabolism. This effect was cell intrinsic and specific to activated effector T cells, as naive T cells and regulatory T cells did not require leptin for metabolic regulation. Importantly, either leptin addition to cultured T cells from fasted animals or leptin injections to fasting animals was sufficient to rescue both T cell metabolic and functional defects. Leptin-mediated metabolic regulation was critical, as transgenic expression of the glucose transporter Glut1 rescued cytokine production of T cells from fasted mice. Together, these data demonstrate that induction of T cell metabolism upon activation is dependent on systemic nutritional status, and leptin links adipocytes to metabolically license activated T cells in states of nutritional sufficiency.

/pdf/leptin-metabolically-licenses-t-cells-for-activation-to-link-koeubloejp.pdf

Leptin Metabolically Licenses T Cells for Activation To Link Nutrition and Immunity

Upon activation, T cells require energy for growth, proliferation, and function. Effector T (Teff) cells, such as Th1 and Th17 cells, utilize high levels of glycolytic metabolism to fuel proliferation and function. In contrast, Treg cells require oxidative metabolism to fuel suppressive function. It remains unknown how Teff/Treg-cell metabolism is altered when nutrients are limited and leptin levels are low. We therefore examined the role of malnutrition and associated hypoleptinemia on Teff versus Treg cells. We found that both malnutrition-associated hypoleptinemia and T cell-specific leptin receptor knockout suppressed Teff-cell number, function, and glucose metabolism, but did not alter Treg-cell metabolism or suppressive function. Using the autoimmune mouse model EAE, we confirmed that fasting-induced hypoleptinemia altered Teff-cell, but not Treg-cell, glucose metabolism, and function in vivo, leading to decreased disease severity. To explore potential mechanisms, we examined HIF-1α, a key regulator of Th17 differentiation and Teff-cell glucose metabolism, and found HIF-1α expression was decreased in T cell-specific leptin receptor knockout Th17 cells, and in Teff cells from fasted EAE mice, but was unchanged in Treg cells. Altogether, these data demonstrate a selective, cell-intrinsic requirement for leptin to upregulate glucose metabolism and maintain function in Teff, but not Treg cells.

/pdf/leptin-directly-promotes-t-cell-glycolytic-metabolism-to-2tg21g0cpp.pdf

Leptin directly promotes T-cell glycolytic metabolism to drive effector T-cell differentiation in a mouse model of autoimmunity.

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