Dynamic Foxp3-chromatin interaction controls tunable Treg cell function.

Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here, we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3-chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncover dynamic proteins within Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3-chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at the Foxp3 DNA-binding domain destabilize the Foxp3-chromatin association. These representative settings delineate context-dependent Foxp3-chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3-DNA binding, to dynamically regulate Treg cell function according to immunological contexts.

Vapor deposition strategy for implanting isolated Fe sites into papermaking nanofibers-derived N-doped carbon aerogels for liquid Electrolyte-/All-Solid-State Zn-Air batteries.

Single-atom catalysts (SACs), with precisely controlled metal atom distribution and adjustable coordination architecture, have gained intensive concerns as efficient oxygen reduction reaction (ORR) electrocatalysts in Zn-air batteries (ZAB). The attainment of a monodispersed state for metallic atoms anchored on the carbonaceous substrate remains the foremost research priority; however, the persistent challenges lie in the relatively weak metal-support interactions and the instability of captured single atom active sites. Furthermore, in order to achieve rapid transport of O2 and other reactive substances within the carbon matrix, manufacturing SACs based on multi-stage porous carbon substrates is highly anticipated. Here, we propose a methodology for the fabrication of carbon aerogels (CA)-supported SACs utilizing papermaking nanofibers, which incorporates advanced strategies for N-atom self-doping, defect/vacancy introduction, and single-atom interface engineering. Specifically, taking advantages of using green and energy-efficient feedstocks, combining with a direct pore-forming template volatilization and chemical vapor deposition approach, we successfully developed N-doped carbon aerogels immobilized with separated iron sites (Fe-SAC@N/CA-Cd). The obtained Fe-SAC@N/CA-Cd exhibited substantially large specific surface area (SBET = 1173 m2/g) and a multi-level pore structure, which can effectively mitigate the random aggregation of Fe atoms during pyrolysis. As a result, it demonstrated appreciable activity and stability in catalyzing the ORR progress (E1/2 = 0.88 V, Eonset = 0.96 V). Furthermore, the assembled liquid electrolyte-state Zn-air batteries (LES-ZAB) and all-solid-state Zn-air battery (ASS-ZAB) also provides encouraging performance, with a peak power density of 169 mW cm-2 for LES-ZAB and a maximum power density of 124 mW cm-2 for ASS-ZAB.

Antitumor progenitor exhausted CD8+ T cells are sustained by TCR engagement.

The durability of an antitumor immune response is mediated in part by the persistence of progenitor exhausted CD8+ T cells (Tpex). Tpex serve as a resource for replenishing effector T cells and preserve their quantity through self-renewal. However, it is unknown how T cell receptor (TCR) engagement affects the self-renewal capacity of Tpex in settings of continued antigen exposure. Here we use a Lewis lung carcinoma model that elicits either optimal or attenuated TCR signaling in CD8+ T cells to show that formation of Tpex in tumor-draining lymph nodes and their intratumoral persistence is dependent on optimal TCR engagement. Notably, attenuated TCR stimulation accelerates the terminal differentiation of optimally primed Tpex. This TCR-reinforced Tpex development and self-renewal is coupled to proximal positioning to dendritic cells and epigenetic imprinting involving increased chromatin accessibility at Egr2 and Tcf1 target loci. Collectively, this study highlights the critical function of TCR engagement in sustaining Tpex during tumor progression.

Cu/CeO2 catalysts for reverse water gas shift reactions: the effect of the preparation method.

The reverse water gas shift reaction is one of the most prospective CO2 utilization approaches. Cu has excellent selectivity for CO and CeO2 is rich in surface oxygen vacancies for CO2 activation. These unique properties are often used to develop efficient Cu/CeO2 catalysts in RWGS. In this paper, Cu/CeO2 is prepared by plasma-induced micro-combustion. The effect of the subsequent calcination after micro-combustion on the structure and catalytic property is systemically studied. Because of the mild temperature of micro-combustion, highly dispersed Cu species load on the surface of CeO2 for the catalyst without calcination (Cu/CeO2-mc). During calcination, the highly dispersed Cu species form two kinds of species, Cu-Ce solid solution structure and small CuO clusters (Cu/CeO2-mcc). The Cu-Ce solid solution effectively enhances the generation of oxygen vacancies, which improves the adsorption and activation of CO2. The catalytic performance of Cu/CeO2-mcc thereby is superior to Cu/CeO2-mc in RWGS. In situ diffuse reflectance infrared fourier transform spectroscopy analysis demonstrates that the formate pathway is the main mechanism of RWGS. CO2 adsorbed on the surface of Cu/CeO2-mcc mainly forms bidentate species. While monodentate generates on the surface of Cu/CeO2-mc. And decomposes to CO easier than , thus Cu/CeO2-mcc exhibits excellent catalytic properties. This work provides a new approach for structural modulation of catalysts with excellent catalytic performance in RWGS.

Characterization of the MT-2 Treg-like cell line in the presence and absence of forkhead box P3 (FOXP3).

CD4+ forkhead box P3 (FOXP3)+ regulatory T cells (Tregs) are essential in maintaining immune tolerance and suppressing excessive immune responses. Tregs also contribute to tissue repair processes distinct from their roles in immune suppression. For these reasons, Tregs are candidates for targeted therapies for inflammatory and autoimmune diseases, and in diseases where tissue damage occurs. MT-2 cells, an immortalized Treg-like cell line, offer a model to study Treg biology and their therapeutic potential. In the present study, we use clustered regularly interspaced palindromic repeats (CRISPR)-mediated knockdown of FOXP3 in MT-2 cells to understand the transcriptional and functional changes that occur when FOXP3 is lost and to compare MT-2 cells with primary human Tregs. We demonstrate that loss of FOXP3 affects the transcriptome of MT-2 cells and that FOXP3's potential downstream targets include a wide range of transcripts that participate in the cell cycle, promote growth and contribute to inflammatory processes, but do not wholly simulate previously reported human primary Treg transcriptional changes in the absence of FOXP3. We also demonstrate that FOXP3 regulates cell cycling and proliferation, expression of molecules crucial to Treg function and MT-2 cell-suppressive activities. Thus, MT-2 cells offer opportunities to address regulatory T-cell functions in vitro.

Utilization of intense pulsed light for hair removal in pediatric auricular reconstruction using tissue expander: A retrospective cohort study.

This study aimed to investigate the safety and efficacy of depilation with intense pulsed light (IPL) in congenital microtia patients during their reconstruction treatment. The hairy skin was treated with the M22TM system (Lumenis, German) using a filter of 695 to 1200 mm. A contact prob with a window of 15 cm × 35 mm or 8 cm × 15 mm was used at a radiant setting of 14 to 15 J/cm2 in the non-expander group and 13 to 14 J/cm2 in the expander group, both in a single pulse mode. The efficiency index of hair removal was classified based on the percentage of hair density reduction as excellent (>75%), good (50-75%), fair (25-50%), poor (<25%). The depilation effect was compared between the 2 groups, and any adverse effects were evaluated. A total of 159 patients were included, with 93 patients in the expander group and 66 in the non-expander group. The reduction of the hair density in the expander group after 3 treatments was higher than that in the non-expander group [82.98 (73.47-89.09)% vs 77.84 (71.50-85.34)%; P < .05, Wilcoxon rank-sum test], as well as the efficiency [excellent cases 68 (73.12%) vs 37 (56.06%); P < .05, Chi-square test]. Four cases of folliculitis, 3 cases of blisters, and no instance of expander exposure and cartilage absorption were observed in this study. Hair removal with IPL is a safe and effective photo-epilation method during all stages of ear reconstruction using tissue expander. Depilation in the skin expansion period resulted in better outcomes after 3 treatments, although after 5 treatments no difference between the 2 groups was observed.

Sn-mediated topological transformation of Archimedean polyhedra of Prussian blue analogues boosts the electrocatalytic performance for alkaline hydrogen production.

The exploitation of an extraordinary and low-cost electrocatalyst to solve energy shortage and environmental pollution issues is crucial. Herein, a topological Archimedean polyhedron of CoFe PBA (Prussian blue analogue) was synthesized via a Sn-induced crystal growth regulation strategy. After phosphating treatment of the as-prepared Sn-CoFe PBA, a Sn-doped binary CoP/FeP hybrid was obtained (Sn-CoP/FeP). Benefiting from the rough polyhedral surface and internal porous structure of Sn-CoP/FeP, when served as a highly efficient electrocatalyst, it exhibited outstanding HER performance, i.e., to drive a current density of 10 mA cm-2, it required a low overpotential of 62 mV in alkaline medium, along with a long-term cycling stability for 35 h. This work is of great significance for the development of indispensable novel catalysts for hydrogen production, and would shed new light on the topology-related performance of electrocatalysts for energy storage and conversion.

Electroactive injectable hydrogel based on oxidized sodium alginate and carboxymethyl chitosan for wound healing.

Electroactive hydrogel is of great significance in restoring wound currents, promoting cell proliferation, and accelerating the wound healing process. However, the poor dispersity and underlying toxicity of electronic conductive fillers and high concentration of ionic conductors in traditional electroactive hydrogel limited its application in medical care. Herein, an electroactive oxidized sodium alginate/carboxymethyl chitosan/silver nanoparticles (OSA/CMCS/AgNPs) hydrogel was constructed with no additional conductive fillers or synthesized conductive polymers being added, in which the dynamic imine bonds were rapidly formed between aldehyde groups in OSA and amino groups in CMCS, and AgNPs were further in situ formed by UV irradiation. The electroactive hydrogel exhibited the injectable property, strong self-healing ability, excellent biocompatibility, and high antibacterial activities. Moreover, the electroactive hydrogel can significantly promote the proliferation of L929 cells under electrical stimulation. Furthermore, the electroactive hydrogel was proved to significantly accelerate the wound healing process in the full-thickness skin defect model, exhibiting anti-inflammation, promoting the fibroblasts proliferation, angiogenesis, and collagen deposition under electrical stimulation. In summary, the current work explored a novel strategy to construct the polysaccharides-based electroactive hydrogel with good biocompatibility and multi-functions, which is promising to be used in deep wound treatment.

Evaluation of the safety and efficacy of a fractional picosecond 1064 nm laser for post-acne erythema in adult Chinese patients.

OBJECTIVE: To evaluate the efficacy and safety of fractional 1064 nm picosecond Nd:YAG laser (FPNYL) in the treatment of post-acne erythema (PAE) of adult Chinese. MATERIALS AND METHODS: A total of 22 patients received 1 session of treatment and were followed up at the eighth week. Primary outcomes were measured by the Clinician erythema assessment scale (CEAS). Secondary outcomes included a global aesthetic improvement scale (GAIS) and patients' assessment of satisfaction on a five-point scale. Pain scores and adverse effects were also evaluated. RESULTS: Twenty-two patients with Fitzpatrick skin types III and IV were enrolled in the study and completed all treatments and follow-up visits. The mean CEAS scores fell from 2.74 ± 0.80 to 1.95 ± 0.75 (p < 0.05). The mean GAIS of PAE improvement was 2.46 ± 0.68. Erythema percentile scores by VISIA increased from 32.63 ± 7.0 to 45.75 ± 11.45 (t = 5.442, p = 0). The patient satisfaction score was 1.86 ± 1.17. The pain scores were 3.27 ± 1.17 for the FPNYL treatment (varied from 2 to 6). There were moderate erythema and oedema, which last for 3.84 ± 0.78 days. There were overall 68.18% (15/22) patients who felt pruritus in different degrees and 27.27% patients who encountered acne eruptions (white head type). No scar, hyperpigmentation or hypopigmentation was found. CONCLUSION: Treatment with fractional 1064 nm picosecond Nd:YAG laser is effective and safe for PAE of Chinese patients.

Identification of wheat seedling varieties based on MssiapNet.

Introduction: In the actual planting of wheat, there are often shortages of seedlings and broken seedlings on long ridges in the field, thus affecting grain yield and indirectly causing economic losses. Variety identification of wheat seedlings using physical methods timeliness and is unsuitable for universal dissemination. Recognition of wheat seedling varieties using deep learning models has high timeliness and accuracy, but fewer researchers exist. Therefore, in this paper, a lightweight wheat seedling variety recognition model, MssiapNet, is proposed. Methods: The model is based on the MobileVit-XS and increases the model's sensitivity to subtle differences between different varieties by introducing the scSE attention mechanism in the MV2 module, so the recognition accuracy is improved. In addition, this paper proposes the IAP module to fuse the identified feature information. Subsequently, training was performed on a self-constructed real dataset, which included 29,020 photographs of wheat seedlings of 29 varieties. Results: The recognition accuracy of this model is 96.85%, which is higher than the other nine mainstream classification models. Although it is only 0.06 higher than the Resnet34 model, the number of parameters is only 1/3 of that. The number of parameters required for MssiapNet is 29.70MB, and the single image Execution time and the single image Delay time are 0.16s and 0.05s. The MssiapNet was visualized, and the heat map showed that the model was superior for wheat seedling variety identification compared with MobileVit-XS. Discussion: The proposed model has a good recognition effect on wheat seedling varieties and uses a few parameters with fast inference speed, which makes it easy to be subsequently deployed on mobile terminals for practical performance testing.

Regulating the electronic and spin structure of endohedral metallofullerenes: a case investigation of Sc3N@C80 and Sc3C2@C80.

The electrochemical and paramagnetic properties of endohedral metallofullerenes (EMFs) have drawn extensive attention due to their huge potential in the fields of molecular devices, biomedicines, quantum information processing, etc. Exohedral modification of the fullerene carbon cage, such as in the classical Prato reaction, is an effective and facile approach to regulate the electronic structure and molecular dynamics of EMFs. In this work, novel pyrrolidine products of Sc3N@C80 and Sc3C2@C80 were successfully synthesized via Prato reactions using L-cysteine and paraformaldehyde. Structure characterizations demonstrated that two regioisomers with a [5,6] and a [6,6] cycloaddition on the Ih-C80 cage were obtained both for Sc3N@C80 and Sc3C2@C80. Besides, the [6,6]-monoadduct of Sc3N@C80 was thermally stable while the [5,6]-monoadduct exhibited a retro-cycloaddition ability to recover the pristine Sc3N@C80. Electrochemical measurements revealed that the redox potential of Sc3N@C80 could be tuned via such exohedral modifications. Furthermore, the paramagnetic property and internal dynamics of the encapsulated Sc3C2 cluster of Sc3C2@C80 can be well-regulated by controlling the spin density of the molecule. The present work could provide a new approach to regulate the electronic and/or spin structure of EMFs.

Heterogeneous Ni3P/Ni nanoparticles with optimized Ni active sites anchored in N-doped mesoporous nanofibers for boosting pH-universal hydrogen evolution.

Developing low-cost, environmentally friendly and efficient non-precious metal electrocatalysts as alternatives to noble metals for the hydrogen evolution reaction (HER) is highly essential for the sustainable advancement of green hydrogen energy. Herein, a novel heterostructured Ni3P/Ni nanoparticle anchored in nitrogen-doped mesoporous carbon nanofibers (Ni3P/Ni@N-CNFs) is prepared by a facile solid-phase calcination protocol. The results demonstrated that benefiting from the intensive electronic coupling effect at the interface of the Ni3P/Ni heterostructure, the electron configuration of the Ni active site is optimized and thus the favorable HER activity. Furthermore, the N-doped carbon nanofiber scaffold with an extensive mesoporous structure endows Ni3P/Ni@N-CNFs with abundant electrochemically active sites together with excellent conductivity and stability, contributing to fast electron/mass transport. As expected, the resultant Ni3P/Ni@N-CNF electrocatalyst exhibited exceptional HER catalytic properties under universal pH conditions, driving a current density of 10 mA cm-2 at pretty low overpotentials of 121 mV, 145 mV and 187 mV in acidic, basic and neutral solutions, respectively, and retaining the catalytic stability for over 60 h. This intriguing work represents a fresh perspective for designing and exploiting highly advanced phosphide electrocatalysts for green hydrogen fuel production.

DNA Methylation in Regulatory T Cell Differentiation and Function: Challenges and Opportunities.

As a bona fide epigenetic marker, DNA methylation has been linked to the differentiation and function of regulatory T (Treg) cells, a subset of CD4 T cells that play an essential role in maintaining immune homeostasis and suppressing autoimmunity and antitumor immune response. DNA methylation undergoes dynamic regulation involving maintenance of preexisting patterns, passive and active demethylation, and de novo methylation. Scattered evidence suggests that these processes control different stages of Treg cell lifespan ranging from lineage induction to cell fate maintenance, suppression of effector T cells and innate immune cells, and transdifferentiation. Despite significant progress, it remains to be fully explored how differential DNA methylation regulates Treg cell fate and immunological function. Here, we review recent progress and discuss the questions and challenges for further understanding the immunological roles and mechanisms of dynamic DNA methylation in controlling Treg cell differentiation and function. We also explore the opportunities that these processes offer to manipulate Treg cell suppressive function for therapeutic purposes by targeting DNA methylation.

Metal-Molecule-Metal Junctions on Self-Assembled Monolayers Made with Selective Electroless Deposition.

Electronic transport through molecular-scale devices has been studied extensively for its extraordinary dimension superiority. Assembling such devices into large-scale functional circuits is crucial since the molecular tunnel junctions must be reliable, stable and reproducible during technological applications. In ideal circumstances, the device architecture should be designed such that the metal-molecule-metal (MMM) junctions can be analyzed by the more sensitive four point probe system. In this paper, we expound a delicate method to manufacture molecular junctions, which show excellent stability and reproducibility with high yields (>91 per cent). We form self-assembled monolayers (SAMs) on conductive Au thin film by microcontact printing and then generate robust covalently bound metal thin film electrodes on top of the SAMs by selective electroless deposition. Following MMM junction formation, a photoresist is coated and wells are opened on each feature by lithography. Then, Au thin film, as a permanent top electrode, is deposited into the photolithographically defined well. Conductivity analyzations were carried out on the 50 µm square junctions by the four point probe measurement, and the results showed reproducible tunneling I-V characteristics. This method reveals an approach not only offering a unique vehicle to investigate the electrical properties of molecule ensembles in MMMs, but also making a significant step toward MMM applications at the device level.

Control of Foxp3 induction and maintenance by sequential histone acetylation and DNA demethylation.

Regulatory T (Treg) cells play crucial roles in suppressing deleterious immune response. Here, we investigate how Treg cells are mechanistically induced in vitro (iTreg) and stabilized via transcriptional regulation of Treg lineage-specifying factor Foxp3. We find that acetylation of histone tails at the Foxp3 promoter is required for inducing Foxp3 transcription. Upon induction, histone acetylation signals via bromodomain-containing proteins, particularly targets of inhibitor JQ1, and sustains Foxp3 transcription via a global or trans effect. Subsequently, Tet-mediated DNA demethylation of Foxp3 cis-regulatory elements, mainly enhancer CNS2, increases chromatin accessibility and protein binding, stabilizing Foxp3 transcription and obviating the need for the histone acetylation signal. These processes transform stochastic iTreg induction into a stable cell fate, with the former sensitive and the latter resistant to genetic and environmental perturbations. Thus, sequential histone acetylation and DNA demethylation in Foxp3 induction and maintenance reflect stepwise mechanical switches governing iTreg cell lineage specification.

Fe2P encapsulated in carbon nanowalls decorated with well-dispersed Fe3C nanodots for efficient hydrogen evolution and oxygen reduction reactions.

The development of cost-effective, high-efficiency bifunctional electrocatalysts as alternatives to the state-of-the-art Pt-based materials toward the hydrogen evolution reaction (HER) and oxygen reduction reaction (ORR) is of great significance but still challenging. Herein, an advanced bifunctional electrocatalyst is presented, composed of Fe2P encapsulated in carbon nanowalls decorated with well-dispersed Fe3C nanodots (denoted as Fe2P@Fe3C/CNTs), which is achieved by a novel "inside-out" gas-solid reaction protocol. When functioning as a cathodic catalyst for water splitting, the Fe2P@Fe3C/CNT catalyst needs an ultralow overpotential of 83 mV to deliver a current density of 10 mA cm-2, shows a small Tafel slope of 53 mV dec-1 and ensures long-term stability for over 200 h in an alkaline electrolyte. Notably, the Fe2P@Fe3C/CNT catalyst exhibits an extremely impressive ORR performance with an onset potential (Eonset) of 1.060 V and a half-wave potential (E1/2) of 0.930 V, excellent stability (≈94% activity retention after 36 000 s), and a strong methanol resistance ability, even far outperforming commercial Pt/C (Eonset = 0.955 V, E1/2 = 0.825 V, ≈75% activity retention after less than 3500 s). Such outstanding HER and ORR performances are mainly ascribed to the improved corrosion resistance of the unique Fe2P@C core-shell structures, the abundant catalytically active sites of ultrasmall Fe3C nanodots incorporated in carbon nanowalls, and the good electrical conductivity of 2D graphitic carbon nanotubes used as a support.

Enhanced Electrocatalytic Activity of Nickel Cobalt Phosphide Nanoparticles Anchored on Porous N-Doped Fullerene Nanorod for Efficient Overall Water Splitting.

Design and fabrication of bifunctional efficient and durable noble-metal-free electrocatalyst for hydrogen and oxygen evolution is highly desirable and challenging for overall water splitting. Herein, a novel hybrid nanostructure with Ni2P/CoP nanoparticles decorated on a porous N-doped fullerene nanorod (p-NFNR@Ni-Co-P) was developed as a bifunctional electrocatalyst. Benefiting from the electric current collector (ECC) effect of FNR for the active Ni2P/CoP nanoparticles, the p-NFNR@Ni-Co-P exhibited outstanding electrocatalytic performance for overall water splitting in alkaline medium. To deliver a current density of 10 mA cm-2, the electrolytic cell assembled by p-NFNR@Ni-Co-P merely required a potential as low as 1.62 V, superior to the benchmark noble-metal-based electrocatalyst. Experimental and theoretical results demonstrated that the surface engineered FNR serving as an ECC played a critical role in accelerating the charge transfer during the electrocatalytic reaction. The present work paves the way for fullerene nanostructures in the realm of energy conversion and storage.

Vanadium -mediated ultrafine Co/Co9S8 nanoparticles anchored on Co-N-doped porous carbon enable efficient hydrogen evolution and oxygen reduction reactions.

Developing cost-effective, highly-active and robust electrocatalysts is of vital importance to supersede noble-metal ones for both hydrogen evolution reactions (HERs) and oxygen reduction reactions (ORRs). Herein, a unique vanadium-mediated space confined strategy is reported to construct a composite structure involving Co/Co9S8 nanoparticles anchored on Co-N-doped porous carbon (VCS@NC) as bifunctional electrocatalysts toward HER and ORR. Benefitting from the ultrafine nanostructure, abundant Co-Nx active sites, large specific surface area and defect-rich carbon framework, the resultant VCS@NC exhibits unexceptionable HER catalytic activity, needing extremely low HER overpotentials in pH-universal media (alkaline: 117 mV, acid: 178 mV, neutral: 210 mV) at a current density of 10 mA cm-2, paralleling at least 100 h catalytic durability. Notably, the VCS@NC catalyst delivers high-efficiency ORR performance in alkaline solution, accompanied with a quite high half wave potential of 0.901 V, far overmatching the commercial Pt/C catalyst. Our research opens up novel insight into engineering highly-efficient multifunctional non-precious metal electrocatalysts by a metal-mediated space-confined strategy in energy storage and conversion system.

Regulatory T cells function in established systemic inflammation and reverse fatal autoimmunity.

The immunosuppressive function of regulatory T (Treg) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced ablation of Treg cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from Treg cell paucity, highlighting a vital function of Treg cells in preventing fatal autoimmune inflammation. However, a major question remains whether Treg cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate Treg cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of rescued Treg cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease and provided long-term protection against them. Thus, Treg cells are functional in settings of established broad-spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.

Foxp3 enhancers synergize to maximize regulatory T cell suppressive capacity.

T reg cells bearing a diverse antigen receptor repertoire suppress pathogenic T cells and maintain immune homeostasis during their long lifespan. How their robust function is determined genetically remains elusive. Here, we investigate the regulatory space of the cis-regulatory elements of T reg lineage-specifying factor Foxp3. Foxp3 enhancers are known as distinct readers of environmental cues controlling T reg cell induction or lineage stability. However, their single deficiencies cause mild, if any, immune dysregulation, leaving the key transcriptional mechanisms determining Foxp3 expression and thereby T reg cell suppressive capacity uncertain. We examined the collective activities of Foxp3 enhancers and found that they coordinate to maximize T reg cell induction, Foxp3 expression level, or lineage stability through distinct modes and that ablation of synergistic enhancers leads to lethal autoimmunity in young mice. Thus, the induction and maintenance of a diverse, stable T reg cell repertoire rely on combinatorial Foxp3 enhancers, suggesting broad, stage-specific, synergistic activities of cell-intrinsic factors and cell-extrinsic cues in determining T reg cell suppressive capacity.