How systemic metabolic alterations during acute infections impact immune cell function remains poorly understood. We found that acetate accumulates in the serum within hours of systemic bacterial ...infections and that these increased acetate concentrations are required for optimal memory CD8+ T cell function in vitro and in vivo. Mechanistically, upon uptake by memory CD8+ T cells, stress levels of acetate expanded the cellular acetyl-coenzyme A pool via ATP citrate lyase and promoted acetylation of the enzyme GAPDH. This context-dependent post-translational modification enhanced GAPDH activity, catalyzing glycolysis and thus boosting rapid memory CD8+ T cell responses. Accordingly, in a murine Listeria monocytogenes model, transfer of acetate-augmented memory CD8+ T cells exerted superior immune control compared to control cells. Our results demonstrate that increased systemic acetate concentrations are functionally integrated by CD8+ T cells and translate into increased glycolytic and functional capacity. The immune system thus directly relates systemic metabolism with immune alertness.
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•Serum acetate levels rapidly increase following systemic bacterial infection•Memory CD8+ T cells take up acetate and expand their acetyl-CoA pool•Increased acetyl-CoA levels catalyze functional activity of GAPDH by acetylation•Augmented glycolytic flux rates boost rapid recall responses of memory CD8+ T cells
How systemic metabolic alterations during acute infections impact immune-cell function remains poorly understood. Hess and colleagues demonstrate that acetate rapidly increases during infections, which drives acetylation of GAPDH in memory CD8+ T cells and thereby catalyzes the rapid recall response.
Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure ...of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.
Glycolysis is linked to the rapid response of memory CD8+ T cells, but the molecular and subcellular structural elements enabling enhanced glucose metabolism in nascent activated memory CD8+ T cells ...are unknown. We found that rapid activation of protein kinase B (PKB or AKT) by mammalian target of rapamycin complex 2 (mTORC2) led to inhibition of glycogen synthase kinase 3β (GSK3β) at mitochondria-endoplasmic reticulum (ER) junctions. This enabled recruitment of hexokinase I (HK-I) to the voltage-dependent anion channel (VDAC) on mitochondria. Binding of HK-I to VDAC promoted respiration by facilitating metabolite flux into mitochondria. Glucose tracing pinpointed pyruvate oxidation in mitochondria, which was the metabolic requirement for rapid generation of interferon-γ (IFN-γ) in memory T cells. Subcellular organization of mTORC2-AKT-GSK3β at mitochondria-ER contact sites, promoting HK-I recruitment to VDAC, thus underpins the metabolic reprogramming needed for memory CD8+ T cells to rapidly acquire effector function.
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•mTORC2, AKT, and GSK3β are present at mitochondria-ER contact sites of CD8+ T cells•mTORC2-activated AKT inhibits GSK3β in nascent activated memory CD8+ T cells•GSK3β inhibition enables binding of HK-I to VDAC, promoting pyruvate oxidation•Pyruvate oxidation is required for rapid generation of IFN-γ in memory T cells
How glucose metabolism enables rapid acquisition of effector function in memory CD8+ T cells remains poorly understood. Bantug et al. demonstrate that mitochondria-endoplasmic reticulum contact sites are signaling hubs that enable the metabolic reprogramming required for rapid CD8+ T cell recall responses.
Summary
T lymphocytes are a critical component of the adaptive immune system mediating protection against infection and malignancy, but also implicated in many immune pathologies. Upon recognition of ...specific antigens T cells clonally expand, traffic to inflamed sites and acquire effector functions, such as the capacity to kill infected and malignantly transformed cells and secrete cytokines to coordinate the immune response. These processes have significant bioenergetic and biosynthetic demands, which are met by dynamic changes in T‐cell metabolism, specifically increases in glucose uptake and metabolism; mitochondrial function; amino acid uptake, and cholesterol and lipid synthesis. These metabolic changes are coordinate by key cellular kinases and transcription factors. Dysregulated T‐cell metabolism is associated with impaired immunity in chronic infection and cancer and conversely with excessive T‐cell activity in autoimmune and inflammatory pathologies. Here we review the key aspects of T‐cell metabolism relevant to their immune function, and discuss evidence for the potential to therapeutically modulate T‐cell metabolism in disease.
Cellular metabolism underpins T‐cell differentiation and function. This review highlights key aspects of T‐cell metabolism relevant to their immune function in a modular manner, and discusses evidence for the potential to therapeutically target T‐cell metabolism in disease.
Natural killer cells lacking expression of CD56 (CD56
NK cells) have been described in chronic HIV and hepatitis C virus infection. Features and functions of CD56
NK cells in the context of latent ...infection with CMV and / or EBV with age are not known. In a cohort of healthy donors >60 years of age, we found that co-infection with CMV and EBV drives expansion of CD56
NK cells. Functionally, CD56
NK cells displayed reduced cytotoxic capacity and IFN-γ production, a feature that was enhanced with CMV / EBV co-infection. Further, the frequency of CD56
NK cells correlated with accumulation of end-stage-differentiated T cells and a reduced CD4 / CD8 T cell ratio, reflecting an immune risk profile. CD56
NK cells had a mature phenotype characterized by low CD57 and KIR expression and lacked characteristics of cell senescence. No changes in their activating NK cell receptor expression, and no upregulation of the negative co-stimulation receptors PD-1 or TIM-3 were observed. In all, our data identify expansion of dysfunctional CD56
NK cells in CMV
EBV
elderly individuals suggesting that these cells may function as shape-shifters of cellular immunity and argue for a previously unrecognized role of EBV in mediating immune risk in the elderly.
The relevance of extracellular magnesium in cellular immunity remains largely unknown. Here, we show that the co-stimulatory cell-surface molecule LFA-1 requires magnesium to adopt its active ...conformation on CD8+ T cells, thereby augmenting calcium flux, signal transduction, metabolic reprogramming, immune synapse formation, and, as a consequence, specific cytotoxicity. Accordingly, magnesium-sufficiency sensed via LFA-1 translated to the superior performance of pathogen- and tumor-specific T cells, enhanced effectiveness of bi-specific T cell engaging antibodies, and improved CAR T cell function. Clinically, low serum magnesium levels were associated with more rapid disease progression and shorter overall survival in CAR T cell and immune checkpoint antibody-treated patients. LFA-1 thus directly incorporates information on the composition of the microenvironment as a determinant of outside-in signaling activity. These findings conceptually link co-stimulation and nutrient sensing and point to the magnesium-LFA-1 axis as a therapeutically amenable biologic system.
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•LFA-1 mediated co-stimulation of CD8+ T cells depends on extracellular magnesium•Magnesium is sensed via LFA-1 and regulates the effector function of CD8+ T cells•Low serum magnesium levels are associated with worse outcomes in cancer immunotherapy•The magnesium-LFA-1 axis has translational potential
The T cell co-stimulatory molecule LFA-1 binds extracellular magnesium ions, allowing it to modulate murine and human CD8+ T cell effector function in response to magnesium levels during normal responses and in the context of immunotherapy.
Serum acetate increases upon systemic infection. Acutely, assimilation of acetate expands the capacity of memory CD8+ T cells to produce IFN-γ. Whether acetate modulates memory CD8+ T cell metabolism ...and function during pathogen re-encounter remains unexplored. Here we show that at sites of infection, high acetate concentrations are being reached, yet memory CD8+ T cells shut down the acetate assimilating enzymes ACSS1 and ACSS2. Acetate, being thus largely excluded from incorporation into cellular metabolic pathways, now had different effects, namely (1) directly activating glutaminase, thereby augmenting glutaminolysis, cellular respiration, and survival, and (2) suppressing TCR-triggered calcium flux, and consequently cell activation and effector cell function. In vivo, high acetate abundance at sites of infection improved pathogen clearance while reducing immunopathology. This indicates that, during different stages of the immune response, the same metabolite—acetate—induces distinct immunometabolic programs within the same cell type.
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•Acetate concentrations are increased at sites of inflammation•TCR signaling and acetate reduce ACSS1/2 expression in memory CD8+ T cells•Glutaminolysis is boosted and calcium flux inhibited by acetate•Local acetate accumulation protects from immunopathology
Balmer et al. uncover that acetate abundance steadily increases at sites of inflammation. Acetate directly affects the activation and function of memory CD8+ T cells by activating glutaminolysis and reducing calcium availability. In vivo, the integrated pro- and anti-inflammatory activities of acetate balance immune control with immunopathology.
The role of mitochondrial biogenesis during naïve to effector differentiation of CD8+ T cells remains ill explored. In this study, we describe a critical role for early mitochondrial biogenesis in ...supporting cytokine production of nascent activated human naïve CD8+ T cells. Specifically, we found that prior to the first round of cell division activated naïve CD8+ T cells rapidly increase mitochondrial mass, mitochondrial respiration, and mitochondrial reactive oxygen species (mROS) generation, which were all inter‐linked and important for CD8+ T cell effector maturation. Inhibition of early mitochondrial biogenesis diminished mROS dependent IL‐2 production – as well as subsequent IL‐2 dependent TNF, IFN‐γ, perforin, and granzyme B production. Together, these findings point to the importance of mitochondrial biogenesis during early effector maturation of CD8+ T cells.
Activation induced mitochondrial biogenesis is important for mROS dependent IL‐2 production in naïve CD8+ T cells. Autocrine IL‐2 signaling is critical for subsequent TNF, IFN‐γ, perforin and granzyme B production. Thus, mitochondrial biogenesis is a requirement for early effector maturation of naïve CD8+ T cells.
Medulloblastoma (MB) comprises four molecularly and genetically distinct subgroups of embryonal brain tumors that develop in the cerebellum. MB mostly affects infants and children and is difficult to ...treat because of frequent dissemination of tumor cells within the leptomeningeal space. A potential promoter of cell dissemination is the c-Met proto-oncogene receptor tyrosine kinase, which is aberrantly expressed in many human tumors including MB. Database analysis showed that c-Met is highly expressed in the sonic hedgehog (SHH) subgroup and in a small subset of Group 3 and Group 4 MB tumors. Using a cell-based three-dimensional cell motility assay combined with live-cell imaging, we investigated whether the c-Met ligand HGF could drive dissemination of MB cells expressing high levels of c-Met, and determined downstream effector mechanisms of this process. We detected variable c-Met expression in different established human MB cell lines, and we found that in lines expressing high c-Met levels, HGF promoted cell dissemination and invasiveness. Specifically, HGF-induced c-Met activation enhanced the capability of the individual cells to migrate in a JNK-dependent manner. Additionally, we identified the Ser/Thr kinase MAP4K4 as a novel driver of c-Met-induced invasive cell dissemination. This increased invasive motility was due to MAP4K4 control of F-actin dynamics in structures required for migration and invasion. Thus, MAP4K4 couples growth factor signaling to actin cytoskeleton regulation in tumor cells, suggesting that MAP4K4 could present a promising novel target to be evaluated for treating growth factor-induced dissemination of MB tumors of different subgroups and of other human cancers.
We investigated the possible modulation of the intestinal contractility by uracil nucleotides (UTP and UDP), using as model the murine small intestine. Contractile activity of a mouse ileum ...longitudinal muscle was examined in vitro as changes in isometric tension. Transcripts encoding for uracil-sensitive receptors was investigated by RT-PCR. UDP induced muscular contractions, sensitive to PPADS, suramin, or MRS 2578, P2Y
6
receptor antagonist, and mimicked by PSB 0474, P2Y
6
-receptor agonist. UTP induced biphasic effects characterized by an early inhibition of the spontaneous contractile activity followed by muscular contraction. UTP excitatory effects were antagonized by PPADS, suramin, but not by MRS 2578, whilst the inhibitory effects were antagonized by PPADS but not by suramin or MRS 2578. UTPγS, P2Y
2
/
4
receptor agonist but not 2-thio-UTP, P2Y
2
receptor agonist, mimicked UTP effects. The inhibitory effects induced by UTP was abolished by ATP desensitization and increased by extracellular acidification. UDP or UTP responses were insensitive to TTX, atropine, or L-NAME antagonized by U-73122, inhibitor of phospholipase C (PLC) and preserved in the presence of nifedipine or low Ca
2+
solution. Transcripts encoding the uracil nucleotide-preferring receptors were expressed in mouse ileum. Functional postjunctional uracil-sensitive receptors are present in the longitudinal muscle of the mouse ileum. Activation of P2Y
6
receptors induces muscular contraction, whilst activation of P2Y
4
receptors leads to inhibition of the contractile activity. Indeed, the presence of atypical UTP-sensitive receptors leading to muscular contraction is suggested. All uracil-sensitive receptors are linked to the PLC pathway.
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