Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos.

CD4+ regulatory T (Treg) cells accumulate in the tumor microenvironment (TME) and suppress the immune system. Whether and how metabolite availability in the TME influences Treg cell differentiation is not understood. Here, we measured 630 metabolites in the TME and found that serine and palmitic acid, substrates required for the synthesis of sphingolipids, were enriched. A serine-free diet or a deficiency in Sptlc2, the rate-limiting enzyme catalyzing sphingolipid synthesis, suppressed Treg cell accumulation and inhibited tumor growth. Sphinganine, an intermediate metabolite in sphingolipid synthesis, physically interacted with the transcription factor c-Fos. Sphinganine c-Fos interactions enhanced the genome-wide recruitment of c-Fos to regions near the transcription start sites of target genes including Pdcd1 (encoding PD-1), which promoted Pdcd1 transcription and increased inducible Treg cell differentiation in vitro in a PD-1-dependent manner. Thus, Sptlc2-mediated sphingolipid synthesis translates the extracellular information of metabolite availability into nuclear signals for Treg cell differentiation and limits antitumor immunity.

High-performance fibre battery with polymer gel electrolyte.

Replacement of liquid electrolytes with polymer gel electrolytes is recognized as a general and effective way of solving safety problems and achieving high flexibility in wearable batteries1-6. However, the poor interface between polymer gel electrolyte and electrode, caused by insufficient wetting, produces much poorer electrochemical properties, especially during the deformation of the battery7-9. Here we report a strategy for designing channel structures in electrodes to incorporate polymer gel electrolytes and to form intimate and stable interfaces for high-performance wearable batteries. As a demonstration, multiple electrode fibres were rotated together to form aligned channels, while the surface of each electrode fibre was designed with networked channels. The monomer solution was effectively infiltrated first along the aligned channels and then into the networked channels. The monomers were then polymerized to produce a gel electrolyte and form intimate and stable interfaces with the electrodes. The resulting fibre lithium-ion battery (FLB) showed high electrochemical performances (for example, an energy density of about 128 Wh kg-1). This strategy also enabled the production of FLBs with a high rate of 3,600 m h-1 per winding unit. The continuous FLBs were woven into a 50 cm × 30 cm textile to provide an output capacity of 2,975 mAh. The FLB textiles worked safely under extreme conditions, such as temperatures of -40 °C and 80 °C and a vacuum of -0.08 MPa. The FLBs show promise for applications in firefighting and space exploration.

Cellular metabolism regulates the differentiation and function of T-cell subsets.

T cells are an important component of adaptive immunity and protect the host from infectious diseases and cancers. However, uncontrolled T cell immunity may cause autoimmune disorders. In both situations, antigen-specific T cells undergo clonal expansion upon the engagement and activation of antigens. Cellular metabolism is reprogrammed to meet the increase in bioenergetic and biosynthetic demands associated with effector T cell expansion. Metabolites not only serve as building blocks or energy sources to fuel cell growth and expansion but also regulate a broad spectrum of cellular signals that instruct the differentiation of multiple T cell subsets. The realm of immunometabolism research is undergoing swift advancements. Encapsulating all the recent progress within this concise review in not possible. Instead, our objective is to provide a succinct introduction to this swiftly progressing research, concentrating on the metabolic intricacies of three pivotal nutrient classes-lipids, glucose, and amino acids-in T cells. We shed light on recent investigations elucidating the roles of these three groups of metabolites in mediating the metabolic and immune functions of T cells. Moreover, we delve into the prospect of "editing" metabolic pathways within T cells using pharmacological or genetic approaches, with the aim of synergizing this approach with existing immunotherapies and enhancing the efficacy of antitumor and antiinfection immune responses.

The malate shuttle detoxifies ammonia in exhausted T cells by producing 2-ketoglutarate.

The malate shuttle is traditionally understood to maintain NAD+/NADH balance between the cytosol and mitochondria. Whether the malate shuttle has additional functions is unclear. Here we show that chronic viral infections induce CD8+ T cell expression of GOT1, a central enzyme in the malate shuttle. Got1 deficiency decreased the NAD+/NADH ratio and limited antiviral CD8+ T cell responses to chronic infection; however, increasing the NAD+/NADH ratio did not restore T cell responses. Got1 deficiency reduced the production of the ammonia scavenger 2-ketoglutarate (2-KG) from glutaminolysis and led to a toxic accumulation of ammonia in CD8+ T cells. Supplementation with 2-KG assimilated and detoxified ammonia in Got1-deficient T cells and restored antiviral responses. These data indicate that the major function of the malate shuttle in CD8+ T cells is not to maintain the NAD+/NADH balance but rather to detoxify ammonia and enable sustainable ammonia-neutral glutamine catabolism in CD8+ T cells during chronic infection.

Highly Reliable Textile-Type Memristor by Designing Aligned Nanochannels.

Information-processing devices are the core components of modern electronics. Integrating them into textiles is the indispensable demand for electronic textiles to form close-loop functional systems. Memristors with crossbar configuration are regarded as promising building blocks to design woven information-processing devices that seamlessly unify with textiles. However, the memristors always suffer from severe temporal and spatial variations due to the random growth of conductive filaments during filamentary switching processes. Here, inspired by the ion nanochannels across synaptic membranes, a highly reliable textile-type memristor made of Pt/CuZnS memristive fiber with aligned nanochannels, showing small set voltage variation (<5.6%) under ultralow set voltage (≈0.089 V), high on/off ratio (≈106 ), and low power consumption (0.1 nW), is reported. Experimental evidence indicate that nanochannels with abundant active S defects can anchor silver ions and confine their migrations to form orderly and efficient conductive filaments. Such memristive performances enable the resultant textile-type memristor array to have high device-to-device uniformity and process complex physiological data like brainwave signals with high recognition accuracy (95%). The textile-type memristor arrays are mechanically durable to withstand hundreds of bending and sliding deformations, and seamlessly unified with sensing, power-supplying, and displaying textiles/fibers to form all-textile integrated electronic systems for new generation human-machine interactions.

Regulatory T cell-derived interleukin-15 promotes the diversity of immunological memory.

While the immunosuppressive function of regulatory T (Treg) cells has been extensively studied, their immune-supportive roles have been less well investigated. Using a lymphocytic choriomeningitis virus (LCMV) Armstrong infection mouse model, we found that Treg cell-derived interleukin (IL)-15 is required for long-term maintenance of the KLRG1+ IL-7Rα- CD62L- terminal effector memory CD8+ T (tTEM) cell subset, but dispensable for the suppressive function of Treg cells themselves. In contrast, deletion of Il15 from other sources, including myeloid cells and muscles, did not affect the composition of the memory CD8+ T cell pool. Our findings identify Treg cells as an essential IL-15 source maintaining tTEM cells and suggest that Treg cells promote the diversity of immunological memory.

A legume kinesin controls vacuole morphogenesis for rhizobia endosymbiosis.

Symbioses between legumes and rhizobia require establishment of the plant-derived symbiosome membrane, which surrounds the rhizobia and accommodates the symbionts by providing an interface for nutrient and signal exchange. The host cytoskeleton and endomembrane trafficking systems play central roles in the formation of a functional symbiotic interface for rhizobia endosymbiosis; however, the underlying mechanisms remain largely unknown. Here we demonstrate that the nodulation-specific kinesin-like calmodulin-binding protein (nKCBP), a plant-specific microtubule-based kinesin motor, controls central vacuole morphogenesis in symbiotic cells in Medicago truncatula. Phylogenetic analysis further indicated that nKCBP duplication occurs solely in legumes of the clade that form symbiosomes. Knockout of nKCBP results in central vacuole deficiency, defective symbiosomes and abolished nitrogen fixation. nKCBP decorates linear particles along microtubules, and crosslinks microtubules with the actin cytoskeleton, to control central vacuole formation by modulating vacuolar vesicle fusion in symbiotic cells. Together, our findings reveal that rhizobia co-opted nKCBP to achieve symbiotic interface formation by regulating cytoskeletal assembly and central vacuole morphogenesis during nodule development.

CD8 agonism functionally activates memory T cells and enhances antitumor immunity.

Memory CD8+ T cells mature after antigen clearance and ultimately express CD8 protein at levels higher than those detected in effector CD8+ T cells. However, it is not clear whether engagement of CD8 in the absence of antigenic stimulation will result in the functional activation of T cells. Here, we found that CD8 antibody-mediated activation of memory CD8+ T cells triggered T cell receptor (TCR) downstream signaling, enhanced T cell-mediated cytotoxicity and promoted effector cytokine production in a glucose- and glutamine-dependent manner. Furthermore, pretreatment of memory CD8+ T cells with an agonistic anti-CD8 antibody enhanced their tumoricidal activity in vitro and in vivo. From these studies, we conclude that CD8 agonism activates glucose and glutamine metabolism in memory T cells and enhances the efficacy of memory T cell-based cancer immunotherapy.

Rgs16 promotes antitumor CD8+ T cell exhaustion.

T cells become functionally exhausted in tumors, limiting T cell-based immunotherapies. Although several transcription factors regulating the exhausted T (Tex) cell differentiation are known, comparatively little is known about the regulators of Tex cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed Tex cell survival in tumors. By performing lineage tracing using reporter mice in which mCherry marked Rgs16-expressing cells, we identified that Rgs16+CD8+ tumor-infiltrating lymphocytes (TILs) were terminally differentiated, expressed low levels of T cell factor 1 (Tcf1), and underwent apoptosis as early as 6 days after the onset of Rgs16 expression. Rgs16 deficiency inhibited CD8+ T cell apoptosis and promoted antitumor effector functions of CD8+ T cells. Furthermore, Rgs16 deficiency synergized with programmed cell death protein 1 (PD-1) blockade to enhance antitumor CD8+ T cell responses. Proteomics revealed that Rgs16 interacted with the scaffold protein IQGAP1, suppressed the recruitment of Ras and B-Raf, and inhibited Erk1 activation. Rgs16 deficiency enhanced antitumor CD8+ TIL survival in an Erk1-dependent manner. Loss of function of Erk1 decreased antitumor functions of Rgs16-deficient CD8+ T cells. RGS16 mRNA expression levels in CD8+ TILs of patients with melanoma negatively correlated with genes associated with T cell stemness, such as SELL, TCF7, and IL7R, and predicted low responses to PD-1 blockade. This study uncovers Rgs16 as an inhibitor of Tex cell survival in tumors and has implications for improving T cell-based immunotherapies.

Industrial scale production of fibre batteries by a solution-extrusion method.

Fibre batteries are of significant interest because they can be woven into flexible textiles to form compact, wearable and light-weight power solutions1,2. However, current methods adapted from planar batteries through layer-by-layer coating processes can only make fibre batteries with low production rates, which fail to meet the requirements for real applications2. Here, we present a new and general solution-extrusion method that can produce continuous fibre batteries in a single step at industrial scale. Our three-channel industrial spinneret simultaneously extrudes and combines electrodes and electrolyte of fibre battery at high production rates. The laminar flow between functional components guarantees their seamless interfaces during extrusion. Our method yields 1,500 km of continuous fibre batteries for every spinneret unit, that is, more than three orders of magnitude longer fibres than previously reported1,2. Finally, we show a proof-of-principle for roughly 10 m2 of woven textile for smart tent applications, with a battery with energy density of 550 mWh m-2.

Scalable production of high-performing woven lithium-ion fibre batteries.

Fibre lithium-ion batteries are attractive as flexible power solutions because they can be woven into textiles, offering a convenient way to power future wearable electronics1-4. However, they are difficult to produce in lengths of more than a few centimetres, and longer fibres were thought to have higher internal resistances3,5 that compromised electrochemical performance6,7. Here we show that the internal resistance of such fibres has a hyperbolic cotangent function relationship with fibre length, where it first decreases before levelling off as length increases. Systematic studies confirm that this unexpected result is true for different fibre batteries. We are able to produce metres of high-performing fibre lithium-ion batteries through an optimized scalable industrial process. Our mass-produced fibre batteries have an energy density of 85.69 watt hour per kilogram (typical values8 are less than 1 watt hour per kilogram), based on the total weight of a lithium cobalt oxide/graphite full battery, including packaging. Its capacity retention reaches 90.5% after 500 charge-discharge cycles and 93% at 1C rate (compared with 0.1C rate capacity), which is comparable to commercial batteries such as pouch cells. Over 80 per cent capacity can be maintained after bending the fibre for 100,000 cycles. We show that fibre lithium-ion batteries woven into safe and washable textiles by industrial rapier loom can wirelessly charge a cell phone or power a health management jacket integrated with fibre sensors and a textile display.

Large-area display textiles integrated with functional systems.

Displays are basic building blocks of modern electronics1,2. Integrating displays into textiles offers exciting opportunities for smart electronic textiles-the ultimate goal of wearable technology, poised to change the way in which we interact with electronic devices3-6. Display textiles serve to bridge human-machine interactions7-9, offering, for instance, a real-time communication tool for individuals with voice or speech difficulties. Electronic textiles capable of communicating10, sensing11,12 and supplying electricity13,14 have been reported previously. However, textiles with functional, large-area displays have not yet been achieved, because it is challenging to obtain small illuminating units that are both durable and easy to assemble over a wide area. Here we report a 6-metre-long, 25-centimetre-wide display textile containing 5 × 105 electroluminescent units spaced approximately 800 micrometres apart. Weaving conductive weft and luminescent warp fibres forms micrometre-scale electroluminescent units at the weft-warp contact points. The brightness between electroluminescent units deviates by less than 8 per cent and remains stable even when the textile is bent, stretched or pressed. Our display textile is flexible and breathable and withstands repeated machine-washing, making it suitable for practical applications. We show that an integrated textile system consisting of display, keyboard and power supply can serve as a communication tool, demonstrating the system's potential within the 'internet of things' in various areas, including healthcare. Our approach unifies the fabrication and function of electronic devices with textiles, and we expect that woven-fibre materials will shape the next generation of electronics.

Skeletal muscle antagonizes antiviral CD8+ T cell exhaustion.

CD8+ T cells become functionally impaired or "exhausted" in chronic infections, accompanied by unwanted body weight reduction and muscle mass loss. Whether muscle regulates T cell exhaustion remains incompletely understood. We report that mouse skeletal muscle increased interleukin (IL)-15 production during LCMV clone 13 chronic infection. Muscle-specific ablation of Il15 enhanced the CD8+ T cell exhaustion phenotype. Muscle-derived IL-15 was required to maintain a population of CD8+CD103+ muscle-infiltrating lymphocytes (MILs). MILs resided in a less inflamed microenvironment, expressed more T cell factor 1 (Tcf1), and had higher proliferative potential than splenic T cells. MILs differentiated into functional effector T cells after reentering lymphoid tissues. Increasing muscle mass via muscle-specific inhibition of TGFß signaling enhanced IL-15 production and antiviral CD8+ T cell responses. We conclude that skeletal muscle antagonizes T cell exhaustion by protecting T cell proliferative potential from inflammation and replenishing the effector T cell progeny pool in lymphoid organs.

T Cell Factor 1 Suppresses CD103+ Lung Tissue-Resident Memory T Cell Development.

T cell factor 1 (Tcf1) promotes the central memory CD8+ T (TCM) cell differentiation and stemness in lymphoid tissues after systemic infections. It remains unclear whether Tcf1 regulates the CD103high tissue-resident memory CD8+ T (TRM) cell formation in non-lymphoid tissues after mucosal infections. We find that Tcf1 is progressively decreased during lung TRM cell formation. Abrogation of transforming growth factor ß (TGF-ß) signaling is associated with a loss of CD103+ and reciprocal gain of Tcf1+ cells among TRM precursors in vivo. T-cell-specific ablation of Tcf7 enhances CD103 protein expression in TRM cells and precursors and increases TRM cell numbers after primary and secondary infections. Tcf1 directly binds to the Itgae (encoding CD103) locus and partly inhibits TGF-ß-induced CD103 expression. Our study suggests that memory T cell tissue residency and homeostatic proliferation are reciprocally regulated by Tcf1. Tcf1 may play either immunosupportive or immunosuppressive roles in CD8+ T cells, depending on systemic or mucosal infections.

Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.

Patients with the neurological disorder HSAN-I suffer frequent infections, attributed to a lack of pain sensation and failure to seek care for minor injuries. Whether protective CD8+ T cells are affected in HSAN-I patients remains unknown. Here, we report that HSAN-I-associated mutations in serine palmitoyltransferase subunit SPTLC2 dampened human T cell responses. Antigen stimulation and inflammation induced SPTLC2 expression, and murine T-cell-specific ablation of Sptlc2 impaired antiviral-T-cell expansion and effector function. Sptlc2 deficiency reduced sphingolipid biosynthetic flux and led to prolonged activation of the mechanistic target of rapamycin complex 1 (mTORC1), endoplasmic reticulum (ER) stress, and CD8+ T cell death. Protective CD8+ T cell responses in HSAN-I patient PBMCs and Sptlc2-deficient mice were restored by supplementing with sphingolipids and pharmacologically inhibiting ER stress-induced cell death. Therefore, SPTLC2 underpins protective immunity by translating extracellular stimuli into intracellular anabolic signals and antagonizes ER stress to promote T cell metabolic fitness.

Regulatory T cells sense effector T-cell activation through synchronized JunB expression.

To maintain immune tolerance, effector T-cell (Teff) responses must be checked by the regulatory T cells (Tregs) in time. It remains incompletely understood how Tregs sense real-time Teff activation. Here, we report that the AP-1 transcription factor JunB, which is induced in Teffs upon T-cell receptor (TCR) activation, is also increased in Tregs by TCR stimuli. Treg-specific deletion of Junb impairs Treg identity, causes uncontrolled inflammatory cytokine production by Teffs and leads to the T-box transcription factor T-bet-dependent spontaneous inflammation. Furthermore, JunB deficiency in Tregs unleashes antitumor Teff responses in a mouse model of melanoma. We conclude that JunB alarms Tregs of the emerging Teff activation and synchronizes immune regulation with the immune reaction in autoimmunity and cancer.

HIV-1 Nef Disrupts CD4+ T Lymphocyte Polarity, Extravasation, and Homing to Lymph Nodes via Its Nef-Associated Kinase Complex Interface.

HIV-1 Nef is a multifunctional protein that optimizes virus spread and promotes immune evasion of infected cells to accelerate disease progression in AIDS patients. As one of its activities, Nef reduces the motility of infected CD4+ T lymphocytes in confined space. In vivo, Nef restricts T lymphocyte homing to lymph nodes as it reduces the ability for extravasation at the diapedesis step. Effects of Nef on T lymphocyte motility are typically mediated by its ability to reduce actin remodeling. However, interference with diapedesis does not depend on residues in Nef required for inhibition of host cell actin dynamics. In search for an alternative mechanism by which Nef could alter T lymphocyte extravasation, we noted that the viral protein interferes with the polarization of primary human CD4+ T lymphocytes upon infection with HIV-1. Expression of Nef alone is sufficient to disrupt T cell polarization, and this effect is conserved among lentiviral Nef proteins. Nef acts by arresting the oscillation of CD4+ T cells between polarized and nonpolarized morphologies. Mapping studies identified the binding site for the Nef-associated kinase complex (NAKC) as critical determinant of this Nef activity and a NAKC-binding-deficient Nef variant fails to impair CD4+ T lymphocyte extravasation and homing to lymph nodes. These results thus imply the disruption of T lymphocyte polarity via its NAKC binding site as a novel mechanism by which lentiviral Nef proteins alter T lymphocyte migration in vivo.

Multicolor, Fluorescent Supercapacitor Fiber.

Fiber-shaped supercapacitors have attracted broad attentions from both academic and industrial communities due to the demonstrated potentials as next-generation power modules. However, it is important while remains challenging to develop dark-environment identifiable supercapacitor fibers for enhancement on operation convenience and security in nighttime applications. Herein, a novel family of colorful fluorescent supercapacitor fibers has been produced from aligned multi-walled carbon nanotube sheets. Fluorescent dye particles are introduced and stably anchored on the surfaces of aligned multi-walled carbon nanotubes to prepare hybrid fiber electrodes with a broad range of colors from red to purple. The fluorescent component in the dye introduces fluorescent indication capability to the fiber, which is particularly promising for flexible and wearable devices applied in dark environment. In addition, the colorful fluorescent supercapacitor fibers also maintain high electrochemical performance under cyclic bending and charge-discharge processes.

Endothelial APLNR regulates tissue fatty acid uptake and is essential for apelin's glucose-lowering effects.

Treatment of type 2 diabetes mellitus continues to pose an important clinical challenge, with most existing therapies lacking demonstrable ability to improve cardiovascular outcomes. The atheroprotective peptide apelin (APLN) enhances glucose utilization and improves insulin sensitivity. However, the mechanism of these effects remains poorly defined. We demonstrate that the expression of APLNR (APJ/AGTRL1), the only known receptor for apelin, is predominantly restricted to the endothelial cells (ECs) of multiple adult metabolic organs, including skeletal muscle and adipose tissue. Conditional endothelial-specific deletion of Aplnr (AplnrECKO ) resulted in markedly impaired glucose utilization and abrogation of apelin-induced glucose lowering. Furthermore, we identified inactivation of Forkhead box protein O1 (FOXO1) and inhibition of endothelial expression of fatty acid (FA) binding protein 4 (FABP4) as key downstream signaling targets of apelin/APLNR signaling. Both the Apln-/- and AplnrECKO mice demonstrated increased endothelial FABP4 expression and excess tissue FA accumulation, whereas concurrent endothelial Foxo1 deletion or pharmacologic FABP4 inhibition rescued the excess FA accumulation phenotype of the Apln-/- mice. The impaired glucose utilization in the AplnrECKO mice was associated with excess FA accumulation in the skeletal muscle. Treatment of these mice with an FABP4 inhibitor abrogated these metabolic phenotypes. These findings provide mechanistic insights that could greatly expand the therapeutic repertoire for type 2 diabetes and related metabolic disorders.

Electrical Switchability and Dry-Wash Durability of Conductive Textiles.

There is growing interest in the area of conductive textiles in the scientific and industrial community. Herein, we successfully prepared a conductive textile via covalently grafting polyaniline (PANI) onto cotton by a multi-step treatment process. The conductivity of the resultant fabric could be tuned by immersing in water having different pH values. The conductive and insulating properties of the textile could be conveniently switched by alternately immersing in acidic and alkaline bath solutions. Most importantly, the resultant conductive fabrics were able to withstand 40 simulated dry-wash cycles, with almost no decay in the electrical conductivity, indicating their excellent dry-wash durability. The present strategy for fabricating conductive fabrics with excellent switchability of electrical properties and dry-wash durability is expected to provide inspiration for the production of multifunctional conductive textiles for use in hash or sensitive conditions.