The effects of virtual reality interventions on occupational participation and distress from symptoms in palliative care patients: A pilot study.

BACKGROUND: Virtual reality (VR) offers the prospect of a safe and effective adjunct therapeutic modality to promote mental health and reduce distress from symptoms in palliative care patients. Common physiological and psychological symptoms experienced at the end of life may impact the person's participation in day-to-day activities that bring them meaning. The purpose of this study was to examine the effect of VR interventions on occupational participation and distress from symptoms. OBJECTIVES: To describe the stimulus, results, and learnings from a single-site pilot study of virtual reality therapy in a specialist palliative care setting. METHODS: Participants engaged in a VR session lasting from 9 to 30 minutes related to coping with pain, inner peace and mindfulness, adventure, and bucket list. METHODS MEASURES: The pilot prospective quantitative observational cohort study was conducted from November 2021 through March 2022 using a pre-post VR intervention research design. Quantitative data was collected using patient-rated assessments and a wireless pulse oximeter. Occupational performance, satisfaction, and distress symptoms were measured using the Canadian Occupational Performance Measure and the Palliative Care Outcomes Collaboration Symptom Assessment Scale (PCOC SAS). The intervention and study design adhered to international guidelines. RESULTS: Ten participants engaged in the VR interventions. Data showed significantly improved occupational performance and satisfaction scores (p < .001), decreases in PCOC SAS distress from pain (p = .01), fatigue (p < .001), and heart rate (p = .018). No adverse side effects were observed. SIGNIFICANCE OF RESULTS: Outcomes included an analysis of virtual reality's effectiveness to alleviate symptom burden and increase occupational participation for palliative care patients. Of specific interest to the research team was the application of virtual reality in a community-based and inpatient palliative care context to supplement allied health services and its feasibility of integration into standard palliative care. CONCLUSION: VR therapy showed positive improvements in the participants' occupational performance, satisfaction, and distress from pain and fatigue.

Acod1 expression in cancer cells promotes immune evasion through the generation of inhibitory peptides.

Targeting programmed cell death protein 1 (PD-1) is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment. Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to αPD-1, as decreasing Acod1 levels in αPD-1-resistant cancer cells can sensitize tumors to αPD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naive CD8+ T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8+ T cell proliferation is not dependent on the secretion of ITA but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy.

Quantitative Analysis of Autophagy in Single Cells: Differential Response to Amino Acid and Glucose Starvation.

Autophagy is a highly conserved, intracellular recycling process by which cytoplasmic contents are degraded in the lysosome. This process occurs at a low level constitutively; however, it is induced robustly in response to stressors, in particular, starvation of critical nutrients such as amino acids and glucose. That said, the relative contribution of these inputs is ambiguous and many starvation medias are poorly defined or devoid of multiple nutrients. Here, we sought to generate a quantitative catalog of autophagy across multiple stages and in single, living cells under normal growth conditions as well as in media starved specifically of amino acids or glucose. We found that autophagy is induced by starvation of amino acids, but not glucose, in U2OS cells, and that MTORC1-mediated ULK1 regulation and autophagy are tightly linked to amino acid levels. While autophagy is engaged immediately during amino acid starvation, a heightened response occurs during a period marked by transcriptional upregulation of autophagy genes during sustained starvation. Finally, we demonstrated that cells immediately return to their initial, low-autophagy state when nutrients are restored, highlighting the dynamic relationship between autophagy and environmental conditions. In addition to sharing our findings here, we provide our data as a high-quality resource for others interested in mathematical modeling or otherwise exploring autophagy in individual cells across a population.

High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling.

Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

Acod1 Expression in Cancer Cells Promotes Immune Evasion through the Generation of Inhibitory Peptides.

Targeting PD-1 is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment (TME). Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to αPD-1, as decreasing Acod1 levels in αPD-1 resistant cancer cells can sensitize tumors to αPD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naïve CD8+ T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8+ T cell proliferation is not dependent on secretion of ITA, but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy.

Ketolysis drives CD8+ T cell effector function through effects on histone acetylation.

Environmental nutrient availability influences T cell metabolism, impacting T cell function and shaping immune outcomes. Here, we identified ketone bodies (KBs)-including ß-hydroxybutyrate (ßOHB) and acetoacetate (AcAc)-as essential fuels supporting CD8+ T cell metabolism and effector function. ßOHB directly increased CD8+ T effector (Teff) cell cytokine production and cytolytic activity, and KB oxidation (ketolysis) was required for Teff cell responses to bacterial infection and tumor challenge. CD8+ Teff cells preferentially used KBs over glucose to fuel the tricarboxylic acid (TCA) cycle in vitro and in vivo. KBs directly boosted the respiratory capacity and TCA cycle-dependent metabolic pathways that fuel CD8+ T cell function. Mechanistically, ßOHB was a major substrate for acetyl-CoA production in CD8+ T cells and regulated effector responses through effects on histone acetylation. Together, our results identify cell-intrinsic ketolysis as a metabolic and epigenetic driver of optimal CD8+ T cell effector responses.

13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8+ T cells.

Infusion of 13C-labeled metabolites provides a gold-standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, acetate) in Listeria monocytogenes (Lm)-infected mice, we demonstrate that CD8+ T effector (Teff) cells utilize metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily towards nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support ATP and de novo pyrimidine synthesis. Additionally, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. Importantly, Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with Teff cell function in vivo.

LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.

Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential.

Reprogramming of iron metabolism confers ferroptosis resistance in ECM-detached cells.

Cancer cells often acquire resistance to cell death programs induced by loss of integrin-mediated attachment to extracellular matrix (ECM). Given that adaptation to ECM-detached conditions can facilitate tumor progression and metastasis, there is significant interest in effective elimination of ECM-detached cancer cells. Here, we find that ECM-detached cells are remarkably resistant to the induction of ferroptosis. Although alterations in membrane lipid content are observed during ECM detachment, it is instead fundamental changes in iron metabolism that underlie resistance of ECM-detached cells to ferroptosis. More specifically, our data demonstrate that levels of free iron are low during ECM detachment because of changes in both iron uptake and iron storage. In addition, we establish that lowering the levels of ferritin sensitizes ECM-detached cells to death by ferroptosis. Taken together, our data suggest that therapeutics designed to kill cancer cells by ferroptosis may be hindered by lack of efficacy toward ECM-detached cells.

A rapid microglial metabolic response controls metabolism and improves memory.

Chronic high-fat feeding triggers widespread metabolic dysfunction including obesity, insulin resistance, and diabetes. While these ultimate pathological states are relatively well understood, we have a limited understanding of how high-fat intake first triggers physiological changes. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on spatial and learning memory. Acute high-fat intake increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation, fission and metabolic skewing towards aerobic glycolysis. These effects are generalized, detectable in the hypothalamus, hippocampus, and cortex all within 1-3 days of HFD exposure. In vivo microglial ablation and conditional DRP1 deletion experiments show that the microglial metabolic response is necessary for the acute effects of HFD. 13C-tracing experiments reveal that in addition to processing via ß-oxidation, microglia shunt a substantial fraction of palmitate towards anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuro-protective metabolite itaconate. Together, these data identify microglial cells as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and liberating the same carbons instead as alternate bioenergetic and protective substrates. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory.

Prior metabolite extraction fully preserves RNAseq quality and enables integrative multi-'omics analysis of the liver metabolic response to viral infection.

Here, we provide an in-depth analysis of the usefulness of single-sample metabolite/RNA extraction for multi-'omics readout. Using pulverized frozen livers of mice injected with lymphocytic choriomeningitis virus (LCMV) or vehicle (Veh), we isolated RNA prior (RNA) or following metabolite extraction (MetRNA). RNA sequencing (RNAseq) data were evaluated for differential expression analysis and dispersion, and differential metabolite abundance was determined. Both RNA and MetRNA clustered together by principal component analysis, indicating that inter-individual differences were the largest source of variance. Over 85% of LCMV versus Veh differentially expressed genes were shared between extraction methods, with the remaining 15% evenly and randomly divided between groups. Differentially expressed genes unique to the extraction method were attributed to randomness around the 0.05 FDR cut-off and stochastic changes in variance and mean expression. In addition, analysis using the mean absolute difference showed no difference in the dispersion of transcripts between extraction methods. Altogether, our data show that prior metabolite extraction preserves RNAseq data quality, which enables us to confidently perform integrated pathway enrichment analysis on metabolomics and RNAseq data from a single sample. This analysis revealed pyrimidine metabolism as the most LCMV-impacted pathway. Combined analysis of genes and metabolites in the pathway exposed a pattern in the degradation of pyrimidine nucleotides leading to uracil generation. In support of this, uracil was among the most differentially abundant metabolites in serum upon LCMV infection. Our data suggest that hepatic uracil export is a novel phenotypic feature of acute infection and highlight the usefulness of our integrated single-sample multi-'omics approach.

Immunometabolism at the crossroads of obesity and cancer-a Keystone Symposia report.

Immunometabolism considers the relationship between metabolism and immunity. Typically, researchers focus on either the metabolic pathways within immune cells that affect their function or the impact of immune cells on systemic metabolism. A more holistic approach that considers both these viewpoints is needed. On September 5-8, 2022, experts in the field of immunometabolism met for the Keystone symposium "Immunometabolism at the Crossroads of Obesity and Cancer" to present recent research across the field of immunometabolism, with the setting of obesity and cancer as an ideal example of the complex interplay between metabolism, immunity, and cancer. Speakers highlighted new insights on the metabolic links between tumor cells and immune cells, with a focus on leveraging unique metabolic vulnerabilities of different cell types in the tumor microenvironment as therapeutic targets and demonstrated the effects of diet, the microbiome, and obesity on immune system function and cancer pathogenesis and therapy. Finally, speakers presented new technologies to interrogate the immune system and uncover novel metabolic pathways important for immunity.

Inhibition of the mitochondrial pyruvate carrier simultaneously mitigates hyperinflammation and hyperglycemia in COVID-19.

The relationship between diabetes and coronavirus disease 2019 (COVID-19) is bidirectional: Although individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyperinflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease after influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602K (MSDC), dampened pulmonary inflammation and promoted lung recovery while concurrently reducing blood glucose levels and hyperlipidemia after viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized hypoxia-inducible factor-1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development after SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.

Microplastics in urban freshwater streams in Adelaide, Australia: A source of plastic pollution in the Gulf St Vincent.

The pollution of marine environments from plastic waste is anticipated to increase with current increases in plastic production. Reciprocally, escalating research efforts provide an improved understanding, monitoring, awareness, and mitigation of plastic contamination. Freshwater streams are recognised as one of the main contributors of microplastic pollution in marine environments. Presented here is the first investigation on the abundance of microplastic contamination (>20 µm and <5 mm) in freshwater streams in Adelaide, Australia. Composite samples were obtained from the sub-surface waters of eight freshwater streams (Magazine Wetland, Torrens River, Brownhill Creek, Sturt River, Field River, Christie Creek, Onkaparinga River and Pedler Creek), just before their connection to the Gulf St Vincent. Microplastics were found in all samples and microplastic abundance was 6.4 ± 5.5 particles.L-1 across all streams, with significant variations. Microplastic abundances found in the freshwater streams of Adelaide were comparatively higher than those found in areas of similar urbanisation, likely due to the varying methodologies used across studies. This work provides evidence, for the first time, of the prevalence of microplastic contamination in the sub-surface waters of eight freshwater streams in metropolitan Adelaide. These findings reinforce the need for long-term and on-going monitoring of freshwater streams for plastic contamination. Furthermore, spatial and temporal monitoring will allow for the identification in changes to the abundances of microplastics discharging from these sources into the Gulf St Vincent and observe if abundances increase or decrease with any future targeted waste management efforts.

Moral injury and psychosocial functioning in health care workers during the COVID-19 pandemic.

Studies of moral injury among nonmilitary samples are scarce despite repeated calls to examine the prevalence and outcomes of moral injury among civilian frontline workers. The purpose of this study was to describe the prevalence of moral injury and to examine its association with psychosocial functioning among health care workers during the COVID-19 pandemic. We surveyed health care workers (N = 480), assessing exposure to potentially morally injurious events (PMIEs) and psychosocial functioning. Data were analyzed using latent class analysis (LCA) to explore patterns of PMIE exposure (i.e., classes) and corresponding psychosocial functioning. The minimal exposure class, who denied PMIE exposure, accounted for 22% of health care workers. The moral injury-other class included those who had witnessed PMIEs for which others were responsible and felt betrayed (26%). The moral injury-self class comprised those who felt they transgressed their own values in addition to witnessing others' transgressions and feeling betrayed (11%). The betrayal-only class included those who felt betrayed by government and community members but otherwise denied PMIE exposure (41%). Those assigned to the moral injury-self class were the most impaired on a psychosocial functioning composite, followed by those assigned to the moral injury-other and betrayal-only classes, and finally the minimal exposure class. Moral injury is prevalent and impairing for health care workers, which establishes a need for interventions with health care workers in organized care settings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A novel automated morphological analysis of Iba1+ microglia using a deep learning assisted model.

There is growing evidence for the key role of microglial functional state in brain pathophysiology. Consequently, there is a need for efficient automated methods to measure the morphological changes distinctive of microglia functional states in research settings. Currently, many commonly used automated methods can be subject to sample representation bias, time consuming imaging, specific hardware requirements and difficulty in maintaining an accurate comparison across research environments. To overcome these issues, we use commercially available deep learning tools Aiforia® Cloud (Aifoira Inc., Cambridge, MA, United States) to quantify microglial morphology and cell counts from histopathological slides of Iba1 stained tissue sections. We provide evidence for the effective application of this method across a range of independently collected datasets in mouse models of viral infection and Parkinson's disease. Additionally, we provide a comprehensive workflow with training details and annotation strategies by feature layer that can be used as a guide to generate new models. In addition, all models described in this work are available within the Aiforia® platform for study-specific adaptation and validation.

An Assessment of the Potential Benefits of Video Consultation in the Emergency Department: Mixed Methods Study.

BACKGROUND: District general hospital emergency departments may refer patients to a tertiary center depending on the information available to a generalist clinician in discussion with a specialist team. If there is uncertainty, the lowest-risk strategy is often to transfer the patient. Video consultation allowing the specialist team to see and talk to the patient and local clinician while still in the emergency department could improve decision-making for patient transfer. OBJECTIVE: The aim of this study is to assess the potential benefit of real-time video consultation between remote specialists and emergency department patients and clinicians across all specialties. METHODS: Detailed patient data were collected prospectively for 6 months (between January 16, 2012, and July 15, 2012) on all patients presenting to a district general hospital emergency department who required input from a specialist team at the nearest tertiary care center. These patients were discussed retrospectively with the specialist teams to determine whether videoconferencing could have benefited their management. The logistics for the use of videoconferencing were explored. RESULTS: A total of 18,799 patients were seen in the emergency department during the study period. Among the 18,799 patients, 413 referrals (2.2%) were made to the tertiary center specialist teams. A review of the patients transferred indicated that 193 (46.7%) of the 413 patients who were referred might have benefited from video consultation (193/18,799, 1% of all patients). If the specialist team could be accessed via videoconferencing only while a senior member was available in the hospital (8:00 AM-10:00 PM), then a maximum of 5 patients per week across all specialties would use the equipment. If 24-hour specialist access was available, this would increase to 7 patients per week. CONCLUSIONS: In regions where there is direct transportation of patients by ambulance to specialist centers and there is a regional picture archiving and communication system in place, video consultation between emergency department patients and specialists has limited potential to improve patient management.

PGC-1ß maintains mitochondrial metabolism and restrains inflammatory gene expression.

Metabolic programming of the innate immune cells known as dendritic cells (DCs) changes in response to different stimuli, influencing their function. While the mechanisms behind increased glycolytic metabolism in response to inflammatory stimuli are well-studied, less is known about the programming of mitochondrial metabolism in DCs. We used lipopolysaccharide (LPS) and interferon-ß (IFN-ß), which differentially stimulate the use of glycolysis and oxidative phosphorylation (OXPHOS), respectively, to identify factors important for mitochondrial metabolism. We found that the expression of peroxisome proliferator-activated receptor gamma co-activator 1ß (PGC-1ß), a transcriptional co-activator and known regulator of mitochondrial metabolism, decreases when DCs are activated with LPS, when OXPHOS is diminished, but not with IFN-ß, when OXPHOS is maintained. We examined the role of PGC-1ß in bioenergetic metabolism of DCs and found that PGC-1ß deficiency indeed impairs their mitochondrial respiration. PGC-1ß-deficient DCs are more glycolytic compared to controls, likely to compensate for reduced OXPHOS. PGC-1ß deficiency also causes decreased capacity for ATP production at steady state and in response to IFN-ß treatment. Loss of PGC-1ß in DCs leads to increased expression of genes in inflammatory pathways, and reduced expression of genes encoding proteins important for mitochondrial metabolism and function. Collectively, these results demonstrate that PGC-1ß is a key regulator of mitochondrial metabolism and negative regulator of inflammatory gene expression in DCs.

Principles of reproducible metabolite profiling of enriched lymphocytes in tumors and ascites from human ovarian cancer.

Identifying metabolites and delineating their immune-regulatory contribution in the tumor microenvironment is an area of intense study. Interrogating metabolites and metabolic networks among immune cell subsets and host cells from resected tissues and fluids of human patients presents a major challenge, owing to the specialized handling of samples for downstream metabolomics. To address this, we first outline the importance of collaborating with a biobank for coordinating and streamlining workflow for point of care, sample collection, processing and cryopreservation. After specimen collection, we describe our 60-min rapid bead-based cellular enrichment method that supports metabolite analysis between T cells and tumor cells by mass spectrometry. We also describe how the metabolic data can be complemented with metabolic profiling by flow cytometry. This protocol can serve as a foundation for interrogating the metabolism of cell subsets from primary human ovarian cancer.

Carbon source availability drives nutrient utilization in CD8+ T cells.

How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8+ T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8+ T cells, with lactate directly fueling the TCA cycle. In fact, CD8+ T cells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate in vitro, with lactate enhancing T cell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8+ T cells by silencing lactate dehydrogenase A (Ldha) impaired both T cell metabolic homeostasis and proliferative expansion in vivo. Together, our data indicate that carbon source availability shapes T cell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8+ effector T cells.