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Vaccination affords protection from disease by activating pathogen-specific immune cells and facilitating the development of persistent immunologic memory toward the vaccine-specific pathogen. Current vaccine regimens are often based on the efficiency of the acute immune response, and not necessarily on the generation of memory cells, in part because the mechanisms underlying the development of efficient immune memory remain incompletely understood. This Review describes recent advances in defining memory T cell metabolism and how metabolism of these cells might be altered in patients affected by mitochondrial diseases or metabolic syndrome, who show higher susceptibility to recurrent infections and higher rates of vaccine failure. It discusses how this new understanding could add to the way we think about immunologic memory, vaccine development, and cancer immunotherapy.

At the centre of the therapeutic dilemma posed by cancer is the question of how to develop more effective treatments that discriminate between normal and cancerous tissues. Decades of research have shown us that universally applicable principles are rare, but two well-accepted concepts have emerged: first, that malignant transformation goes hand in hand with distinct changes in cellular metabolism; second, that the immune system is critical for tumour control and clearance. Unifying our understanding of tumour metabolism with immune cell function may prove to be a powerful approach in the development of more effective cancer therapies. Here, we explore how nutrient availability in the tumour microenvironment shapes immune responses and identify areas of intervention to modulate the metabolic constraints placed on immune cells in this setting.In this Review, Erika Pearce and colleagues detail the metabolic changes that occur in the tumour microenvironment, explaining how these shape immune cell function at these sites. They highlight the potential of targeting these metabolic pathways to treat patients with cancer

Foamy macrophages, which have prominent lipid droplets (LDs), are found in a variety of disease states. Toll-like receptor agonists drive triacylglycerol (TG)-rich LD development in macrophages. Here we explore the basis and significance of this process. Our findings indicate that LD development is the result of metabolic commitment to TG synthesis on a background of decreased fatty acid oxidation. TG synthesis is essential for optimal inflammatory macrophage activation as its inhibition, which prevents LD development, has marked effects on the production of inflammatory mediators, including IL-1β, IL-6 and PGE2, and on phagocytic capacity. The failure of inflammatory macrophages to make PGE2 when TG-synthesis is inhibited is critical for this phenotype, as addition of exogenous PGE2 is able to reverse the anti-inflammatory effects of TG synthesis inhibition. These findings place LDs in a position of central importance in inflammatory macrophage activation. As macrophages switch to a proinflammatory gylcolytic state they start to generate triglyceride-rich lipid droplets, but what function these droplets have in this context is not clear. Here the authors show that this triglyceride synthesis is requisite for prostaglandin E2 production and subsequent inflammatory activation.

Alternatively activated (M2) macrophages use fatty acid oxidation for their metabolic needs. Pearce and colleagues show that triacylglycerols metabolized by lysosomal acid lipase are required for the M2 activation of and function of macrophages. Alternative (M2) activation of macrophages driven via the α-chain of the receptor for interleukin 4 (IL-4Rα) is important for immunity to parasites, wound healing, the prevention of atherosclerosis and metabolic homeostasis. M2 polarization is dependent on fatty acid oxidation (FAO), but the source of the fatty acids that support this metabolic program has not been clear. We found that the uptake of triacylglycerol substrates via the scavenger receptor CD36 and their subsequent lipolysis by lysosomal acid lipase (LAL) was important for the engagement of elevated oxidative phosphorylation, enhanced spare respiratory capacity (SRC), prolonged survival and expression of genes that together define M2 activation. Inhibition of lipolysis suppressed M2 activation during infection with a parasitic helminth and blocked protective responses to this pathogen. Our findings delineate a critical role for cell-intrinsic lysosomal lipolysis in M2 activation.

A characteristic of memory T (T M) cells is their ability to mount faster and stronger responses to reinfection than naïve T (T N) cells do in response to an initial infection. However, the mechanisms that allow this rapid recall are not completely understood. We found that CD8 T M cells have more mitochondrial mass than CD8 T N cells and, that upon activation, the resulting secondary effector T (T E) cells proliferate more quickly, produce more cytokines, and maintain greater ATP levels than primary effector T cells. We also found that after activation, T M cells increase oxidative phosphorylation and aerobic glycolysis and sustain this increase to a greater extent than T N cells, suggesting that greater mitochondrial mass in T M cells not only promotes oxidative capacity, but also glycolytic capacity. We show that mitochondrial ATP is essential for the rapid induction of glycolysis in response to activation and the initiation of proliferation of both T N and T M cells. We also found that fatty acid oxidation is needed for T M cells to rapidly respond upon restimulation. Finally, we show that dissociation of the glycolysis enzyme hexokinase from mitochondria impairs proliferation and blocks the rapid induction of glycolysis upon T-cell receptor stimulation in T M cells. Our results demonstrate that greater mitochondrial mass endows T M cells with a bioenergetic advantage that underlies their ability to rapidly recall in response to reinfection.

Our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still developing. We perform an observational study to investigate seroprevalence and immune responses in subjects professionally exposed to SARS-CoV-2 and their family members (155 individuals; ages 5–79 years). Seropositivity for SARS-CoV-2 Spike glycoprotein aligns with PCR results that confirm the previous infection. Anti-Spike IgG/IgM titers remain high 60 days post-infection and do not strongly associate with symptoms, except for fever. We analyze PBMCs from a subset of seropositive and seronegative adults. TLR7 agonist-activation reveals an increased population of IL-6 + TNF - IL-1β + monocytes, while SARS-CoV-2 peptide stimulation elicits IL-33, IL-6, IFNa2, and IL-23 expression in seropositive individuals. IL-33 correlates with CD4 + T cell activation in PBMCs from convalescent subjects and is likely due to T cell-mediated effects on IL-33-producing cells. IL-33 is associated with pulmonary infection and chronic diseases like asthma and COPD, but its role in COVID-19 is unknown. Analysis of published scRNAseq data of bronchoalveolar lavage fluid (BALF) from patients with mild to severe COVID-19 reveals a population of IL-33-producing cells that increases with the disease. Together these findings show that IL-33 production is linked to SARS-CoV-2 infection and warrant further investigation of IL-33 in COVID-19 pathogenesis and immunity. Our understanding of the immune response to SARS-CoV-2 infection is still incomplete. Here, the authors find that IL-33, produced during immune recall potentially by CD14 + monocytes, correlates with CD4 + T cell activation, anti-SARS-CoV-2 antibody titer, and disease severity in a cohort of convalescent individuals professionally exposed to the virus.

The cell-intrinsic pathways controlling the function of innate lymphoid cells are poorly defined. Artis and colleagues demonstrate that ILC2s selectively express arginase 1 and that this is critical for their bioenergetics, proliferation and function. Group 2 innate lymphoid cells (ILC2s) regulate tissue inflammation and repair after activation by cell-extrinsic factors such as host-derived cytokines. However, the cell-intrinsic metabolic pathways that control ILC2 function are undefined. Here we demonstrate that expression of the enzyme arginase-1 (Arg1) during acute or chronic lung inflammation is a conserved trait of mouse and human ILC2s. Deletion of mouse ILC-intrinsic Arg1 abrogated type 2 lung inflammation by restraining ILC2 proliferation and dampening cytokine production. Mechanistically, inhibition of Arg1 enzymatic activity disrupted multiple components of ILC2 metabolic programming by altering arginine catabolism, impairing polyamine biosynthesis and reducing aerobic glycolysis. These data identify Arg1 as a key regulator of ILC2 bioenergetics that controls proliferative capacity and proinflammatory functions promoting type 2 inflammation.

MZB1 is an endoplasmic reticulum (ER)-resident protein that plays an important role in the humoral immune response by enhancing the interaction of the μ immunoglobulin (Ig) heavy chain with the chaperone GRP94 and by augmenting the secretion of IgM. Here, we show that MZB1 is also expressed in plasmacytoid dendritic cells (pDCs). Mzb1 −/− pDCs have a defect in the secretion of interferon (IFN) α upon Toll-like receptor (TLR) 9 stimulation and a reduced ability to enhance B cell differentiation towards plasma cells. Mzb1 −/− pDCs do not properly expand the ER upon TLR9 stimulation, which may be accounted for by an impaired activation of ATF6, a regulator of the unfolded protein response (UPR). Pharmacological inhibition of ATF6 cleavage in stimulated wild type pDCs mimics the diminished IFNα secretion by Mzb1 −/− pDCs. Thus, MZB1 enables pDCs to secrete high amounts of IFNα by mitigating ER stress via the ATF6-mediated UPR.

Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8 + T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8 + T cell pool. CD8 + T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8 + T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E 2 (PGE 2 ), which drives mitochondrial depolarization in CD8 + T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE 2 sensing promotes CD8 + T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE 2 -autophagy-glutathione axis defines the metabolic adaptation of CD8 + T cells to the intestinal microenvironment, to ultimately influence the T cell pool. CD8 + T cells reprogram their metabolism in response to the gut environment. Upon sensing of PGE 2 , gut CD8 + T cells reduce their mitochondrial content, an event that ultimately shapes the pool of CD8 + T cells in the intestinal tissue.

The behaviour of Dictyostelium discoideum depends on nutrients 1 . When sufficient food is present these amoebae exist in a unicellular state, but upon starvation they aggregate into a multicellular organism 2 , 3 . This biology makes D. discoideum an ideal model for investigating how fundamental metabolism commands cell differentiation and function. Here we show that reactive oxygen species—generated as a consequence of nutrient limitation—lead to the sequestration of cysteine in the antioxidant glutathione. This sequestration limits the use of the sulfur atom of cysteine in processes that contribute to mitochondrial metabolism and cellular proliferation, such as protein translation and the activity of enzymes that contain an iron–sulfur cluster. The regulated sequestration of sulfur maintains D. discoideum in a nonproliferating state that paves the way for multicellular development. This mechanism of signalling through reactive oxygen species highlights oxygen and sulfur as simple signalling molecules that dictate cell fate in an early eukaryote, with implications for responses to nutrient fluctuations in multicellular eukaryotes. Depriving unicellular Dictyostelium discoideum of nutrients generates reactive oxygen species that sequester cysteine within glutathione, which maintains this amoeba in a nonproliferating state that promotes aggregation into a multicellular organism.