Regulatory T cells (Tregs) subdue immune responses. Central to Treg activation are changes in lipid metabolism that support their survival and function. Fatty acid binding proteins (FABPs) are a ...family of lipid chaperones required to facilitate uptake and intracellular lipid trafficking. One family member, FABP5, is expressed in T cells, but its function remains unclear. We show that in Tregs, genetic or pharmacologic inhibition of FABP5 function causes mitochondrial changes underscored by decreased OXPHOS, impaired lipid metabolism, and loss of cristae structure. FABP5 inhibition in Tregs triggers mtDNA release and consequent cGAS-STING-dependent type I IFN signaling, which induces heightened production of the regulatory cytokine IL-10 and promotes Treg suppressive activity. We find evidence of this pathway, along with correlative mitochondrial changes in tumor infiltrating Tregs, which may underlie enhanced immunosuppression in the tumor microenvironment. Together, our data reveal that FABP5 is a gatekeeper of mitochondrial integrity that modulates Treg function.
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•FABP5 inhibition in Tregs alters mitochondria and enhances suppression•Disrupting FABP5 in Tregs results in mtDNA release and type I IFN signaling•cGAS/-STING-dependent type I IFN signals promote Treg IL-10 production•Tumor Tregs exhibit mitochondrial alterations and a type I IFN gene signature
Field et al. show that fatty acid binding protein 5 (FABP5) maintains mitochondrial integrity in regulatory T cells (Tregs). FABP5 inhibition results in mtDNA release, which triggers expression of IL-10 and promotes Treg suppressive capacity. These findings may have implications for therapeutically targeting Tregs in autoimmunity and cancer.
How cells adapt metabolism to meet demands is an active area of interest across biology. Among a broad range of functions, the polyamine spermidine is needed to hypusinate the translation factor ...eukaryotic initiation factor 5A (eIF5A). We show here that hypusinated eIF5A (eIF5AH) promotes the efficient expression of a subset of mitochondrial proteins involved in the TCA cycle and oxidative phosphorylation (OXPHOS). Several of these proteins have mitochondrial targeting sequences (MTSs) that in part confer an increased dependency on eIF5AH. In macrophages, metabolic switching between OXPHOS and glycolysis supports divergent functional fates stimulated by activation signals. In these cells, hypusination of eIF5A appears to be dynamically regulated after activation. Using in vivo and in vitro models, we show that acute inhibition of this pathway blunts OXPHOS-dependent alternative activation, while leaving aerobic glycolysis-dependent classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis.
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•The polyamine synthesis pathway and hypusinated eIF5A modulate mitochondrial OXPHOS•Hypusinated eIF5A maintains TCA cycle and ETC integrity in macrophages•Some mitochondrial enzymes depend on eIF5AH for efficient expression•Inhibition of hypusinated eIF5A blunts macrophage alternative activation
Puleston et al. show that polyamine biosynthesis modulates mitochondrial metabolism through eIF5A hypusination (eIF5AH). They find that inhibiting the polyamine-eIF5A-hypusine pathway blocks OXPHOS-dependent macrophage alternative activation, while leaving aerobic glycolysis-dependent macrophage classical activation intact. These results might have implications for therapeutically controlling macrophage activation by targeting the polyamine-eIF5A-hypusine axis.
The adoption of Warburg metabolism is critical for the activation of macrophages in response to lipopolysaccharide. Macrophages stimulated with lipopolysaccharide increase their expression of ...nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme in NAD
salvage, and loss of NAMPT activity alters their inflammatory potential. However, the events that lead to the cells' becoming dependent on NAD
salvage remain poorly defined. We found that depletion of NAD
and increased expression of NAMPT occurred rapidly after inflammatory activation and coincided with DNA damage caused by reactive oxygen species (ROS). ROS produced by complex III of the mitochondrial electron-transport chain were required for macrophage activation. DNA damage was associated with activation of poly(ADP-ribose) polymerase, which led to consumption of NAD
. In this setting, increased NAMPT expression allowed the maintenance of NAD
pools sufficient for glyceraldehyde-3-phosphate dehydrogenase activity and Warburg metabolism. Our findings provide an integrated explanation for the dependence of inflammatory macrophages on the NAD
salvage pathway.
Polyamine synthesis represents one of the most profound metabolic changes during T cell activation, but the biological implications of this are scarcely known. Here, we show that polyamine metabolism ...is a fundamental process governing the ability of CD4+ helper T cells (TH) to polarize into different functional fates. Deficiency in ornithine decarboxylase, a crucial enzyme for polyamine synthesis, results in a severe failure of CD4+ T cells to adopt correct subset specification, underscored by ectopic expression of multiple cytokines and lineage-defining transcription factors across TH cell subsets. Polyamines control TH differentiation by providing substrates for deoxyhypusine synthase, which synthesizes the amino acid hypusine, and mice in which T cells are deficient for hypusine develop severe intestinal inflammatory disease. Polyamine-hypusine deficiency caused widespread epigenetic remodeling driven by alterations in histone acetylation and a re-wired tricarboxylic acid (TCA) cycle. Thus, polyamine metabolism is critical for maintaining the epigenome to focus TH cell subset fidelity.
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•Polyamines govern the ability of CD4+ T cells to differentiate into distinct subsets•Through the synthesis of hypusine, polyamines direct the T cell epigenome•Loss of polyamines or hypusine perturbs the TCA cycle and histone acetylation•HAT deletion restores TH differentiation in polyamine-deficient cells
The ability of CD4+ T helper cells to develop into specified functional subsets depends upon polyamine-driven metabolic and epigenetic regulation.
Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show ...that in activated CD8
T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8
T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.
Immune responses are dangerous by nature and require regulation to prevent inflammatory and/or autoimmune sequelae and allow healing. CD4+Foxp3+ T cells (Treg cells) play a crucial role in this ...process, and in this edition of Cell Metabolism, Angelin et al. (2017) describe how these cells are metabolically adapted to the job.
Immune responses are dangerous by nature and require regulation to prevent inflammatory and/or autoimmune sequelae and allow healing. CD4+Foxp3+ T cells (Treg cells) play a crucial role in this process, and in this edition of Cell Metabolism, Angelin et al. (2017) describe how these cells are metabolically adapted to the job.
How lipidome changes support CD8
effector T (T
) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated phosphoinositides (PIP
with 3-4 ...double bonds), T
cells have unique PIP
marked by saturated fatty acyl chains (0-2 double bonds). PIP
are precursors for second messengers. Polyunsaturated phosphatidylinositol bisphosphate (PIP
) exclusively supported signaling immediately upon T cell antigen receptor activation. In late T
cells, activity of phospholipase C-γ1, the enzyme that cleaves PIP
into downstream mediators, waned, and saturated PIP
became essential for sustained signaling. Saturated PIP was more rapidly converted to PIP
with subsequent recruitment of phospholipase C-γ1, and loss of saturated PIP
impaired T
cell fitness and function, even in cells with abundant polyunsaturated PIP
. Glucose was the substrate for de novo PIP
synthesis, and was rapidly utilized for saturated PIP
generation. Thus, separate PIP
pools with distinct acyl chain compositions and metabolic dependencies drive important signaling events to initiate and then sustain effector function during CD8+ T cell differentiation.
Vaccine-mediated cancer treatment is unlikely to induce long-term survival unless suppressive mechanisms are overcome. Given the success of antibody-mediated immune checkpoint blockade in relieving ...regulation of endogenous anti-tumor T cell responses in tumor-burdened hosts, we investigated whether checkpoint blockade could improve the efficacy of responses induced with a whole tumor-cell vaccine. We show that administration of a single dose of blocking antibody was sufficient to significantly enhance antitumor activity of the vaccine, inducing complete radiological regression of established intracranial tumors. The antibody or vaccine alone were ineffective in this setting. The antibody had to be administered before, or close to, vaccine administration, suggesting CTLA-4 blockade had an impact on early priming events. The combined treatment resulted in enhanced trapping of leukocytes in the lymphoid tissues, including T cells that had undergone significant proliferation. There were no obvious changes in the stimulatory function of antigen-presenting cells or the number and function of regulatory T cells, suggesting T cells were the targets of the checkpoint blockade. While tumors regressing under combined treatment were highly infiltrated with a variety of leukocytes, tumor eradication was dependent on CD4
+
T cells. Analysis of the TCR repertoire showed that the addition of anti-CTLA-4 at priming reshaped the repertoire of tumor infiltrating T cells. In particular, the oligoclonal populations became greater in magnitude and more diverse in specificity. Using anti-CTLA-4 in a restricted way to promote the priming phase of an anti-cancer vaccine may offer a useful way of harnessing clinical benefit from this powerful agent.
The prognosis for patients with glioblastoma multiforme (GBM) remains extremely poor despite recent treatment advances. There is an urgent need to develop novel therapies for this disease.
We used ...the implantable GL261 murine glioma model to investigate the therapeutic potential of a vaccine consisting of intravenous injection of irradiated whole tumor cells pulsed with the immuno-adjuvant α-galactosylceramide (α-GalCer).
Vaccine treatment alone was highly effective in a prophylactic setting. In a more stringent therapeutic setting, administration of one dose of vaccine combined with depletion of regulatory T cells (Treg) resulted in 43% long-term survival and the disappearance of mass lesions detected by MRI. Mechanistically, the α-GalCer component was shown to act by stimulating "invariant" natural killer-like T cells (iNKT cells) in a CD1d-restricted manner, which in turn supported the development of a CD4(+) T-cell-mediated adaptive immune response. Pulsing α-GalCer onto tumor cells avoided the profound iNKT cell anergy induced by free α-GalCer. To investigate the potential for clinical application of this vaccine, the number and function of iNKT cells was assessed in patients with GBM and shown to be similar to age-matched healthy volunteers. Furthermore, irradiated GBM tumor cells pulsed with α-GalCer were able to stimulate iNKT cells and augment a T-cell response in vitro.
Injection of irradiated tumor cells loaded with α-GalCer is a simple procedure that could provide effective immunotherapy for patients with high-grade glioma.
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