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.
Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development, activation, function, differentiation, ...and survival. After naive T cells are activated, increased demands for metabolic currency in the form of ATP, as well as biomass for cell growth, proliferation, and the production of effector molecules, are met by rewiring cellular metabolism. Consequently, pharmacological strategies are being developed to perturb or enhance selective metabolic processes that are skewed in immune-related pathologies. Here we review the most recent advances describing the metabolic changes that occur during the T cell lifecycle. We discuss how T cell metabolism can have profound effects on health and disease and where it might be a promising target to treat a variety of pathologies.
Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is ...therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer.
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•Acetate restores IFN-γ in TILs and T cells under prolonged glucose-restriction•Acetate promotes histone acetylation and chromatin accessibility in T cells•ACSS expression contributes to optimal effector T cell function during cancer
Qiu et al. show that acetate enhances histone acetylation, chromatin accessibility, and effector function in glucose-restricted CD8+ T cells. The authors find that manipulation of acetate-handling pathways influences cytokine production of tumor-infiltrating CD8+ T cells, which could have therapeutic implications for activating CD8+ T cell effector function in the tumor microenvironment.
Recent warming of the Antarctic Peninsula during austral autumn, winter, and spring has been linked to sea surface temperature (SST) trends in the tropical Pacific and tropical Atlantic, while ...warming of the northeast Peninsula during summer has been linked to a strengthening of westerly winds traversing the Peninsula associated with a positive trend in the Southern Annular Mode (SAM). Here we demonstrate that circulation changes associated with the SAM dominate interannual temperature variability across the entire Antarctic Peninsula during both summer and autumn, while relationships with tropical Pacific SST variability associated with the El Niño–Southern Oscillation (ENSO) are strongest and statistically significant primarily during winter and spring only. We find the ENSO‐Peninsula temperature relationship during autumn to be weak on interannual time scales and regional circulation anomalies associated with the SAM more important for interannual temperature variability across the Peninsula during autumn. Consistent with previous studies, western Peninsula temperatures during autumn, winter, and spring are closely tied to changes in the Amundsen Sea Low (ASL) and associated meridional wind anomalies. The interannual variability of ASL depth is most strongly correlated with the SAM index during autumn, while the ENSO relationship is strongest during winter and spring. Investigation of western and northeast Peninsula temperatures separately reveals that interannual variability of northeast Peninsula temperatures is primarily sensitive to zonal wind anomalies crossing the Peninsula and resultant leeside adiabatic warming rather than to meridional wind anomalies, which is closely tied to variability in the zonal portion of the SAM pattern.
Key Points
Regional circulation anomalies associated with the SAM dominate temporal temperature variability on the Antarctic Peninsula during summer and autumn
ENSO‐Peninsula temperature relationship is strongest on the western Peninsula but statistically significant only during winter and spring
Northeast Peninsula temperatures are dominated by SAM‐related zonal flow and leeside Föhn effects during all seasons
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.
Early reanalyses are less than optimal for investigating the regional effects of ozone depletion on Southern Hemisphere (SH) high-latitude climate because the availability of satellite sounder data ...from 1979 significantly improved their accuracy in data sparse regions, leading to a coincident inhomogeneity. To determine whether current reanalyses are better at SH high-latitudes in the pre-satellite era, here we examine the capabilities of the European Centre for Medium-range Weather Forecasts (ECMWF) fifth generation reanalysis (ERA5), the Twentieth Century Reanalysis version 3 (20CRv3), and the Japanese Meteorological Agency (JMA) 55-year reanalysis (JRA-55) to reproduce and help explain the pronounced change in the relationship between the Southern Annular Mode (SAM) and Antarctic near-surface air temperatures (SAT) between 1950 and 1979 (EARLY period) and 1980–2020 (LATE period). We find that ERA5 best reproduces Antarctic SAT in the EARLY period and is also the most homogeneous reanalysis across the EARLY and LATE periods. ERA5 and 20CRv3 provide a good representation of SAM in both periods with JRA-55 only similarly skilful in the LATE period. Nevertheless, all three reanalyses show the marked change in Antarctic SAM-SAT relationships between the two periods. In particular, ERA5 and 20CRv3 demonstrate the observed switch in the sign of the SAM-SAT relationship in the Antarctic Peninsula: analysis of changes in SAM structure and associated meridional wind anomalies reveal that in these reanalyses positive SAM is linked to cold southerly winds during the EARLY period and warm northerly winds in the LATE period, thus providing a simple explanation for the regional SAM-SAT relationship reversal.
After 1979, statistically significant warming in Antarctica is only observed in austral spring (September–November, SON) across West Antarctica and the Antarctic Peninsula. While previous work has ...linked this warming to reductions in sea ice cover, we note that a substantial (30–60%) portion of the warming is related to changes in the SON atmospheric circulation. In particular, western Antarctic Peninsula warming is consistent with increasing pressure in the South Atlantic, while western West Antarctica warming is tied to a deepening of the Amundsen Sea low near the eastern Ross Sea. While both of these circulation changes are associated with increased warm, northerly flow toward the Antarctic continent, they are connected with different aspects of tropical variability. The increase in pressure in the South Atlantic is associated with a trend toward more La Niña‐like conditions in the tropical Pacific, and an associated Rossby wave train. In contrast, the deepening of the Amundsen Sea low is more strongly tied to a shift in the Pacific Decadal Oscillation (PDO) toward its negative phase since the 1990s. Compared to typical La Niña events, the recent negative PDO events display a different tropical forcing, which drives a Rossby wave train that propagates more meridionally across the South Pacific, culminating in the eastern Ross Sea, rather than in the South Atlantic. The results suggest multiple independent forcing mechanisms governing the SON pressure trends and associated Antarctic Peninsula and West Antarctica warming after 1979, which partially cancel each other out in the Amundsen Sea and portions of eastern West Antarctica.
Key Points
Deepening ASL in Ross Sea influences warming of western West Antarctica
Increasing South Atlantic pressure influencing western Antarctic Peninsula warming
ENSO linked to South Atlantic/Peninsula; PDO linked to ASL/West Antarctica
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.
T helper 2 (Th2) cells are pivotal in the development of allergy. Allergen exposure primes IL-4⁺ Th2 cells in lymph node, but production of effector cytokines including IL-5 and IL-13 is thought to ...require additional signals from antigen and the environment. Here we report that a substantial proportion of naive CD4⁺ T cells in spleen and lymph node express receptors for the epithelium-derived inflammatory cytokine thymic stromal lymphopoietin (TSLP). Culture of naive CD4⁺ T cells in anti-(a)CD3, aCD28, and TSLP-supplemented Th2 conditions enabled the development of a unique population of IL-13-single positive (IL-13-SP) CD4⁺ T cells; TSLP and Th2 conditions were both required for their development. Sorting experiments revealed that IL-13-SP Th2 cells originated from IL-4-negative precursors and coexpressed transcripts for the Th2 cytokines IL-5 and IL-9. In vivo, high TSLP levels acted directly on CD4⁺ T cells to induce the development of IL-13-SP and IL-4⁺IL-13⁺ double-positive populations in lymph node. These cells were phenotypically similar to Th2 effector cells and were CXCR5lowPD1low and expressed low levels of Bcl6 and Il21 transcripts and high levels of Gata3, Il3, and Il5. Our findings suggest a role of TSLP in directly promoting Th2 cell effector function and support the notion of TSLP as a key driver of Th2 inflammation.
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