Control Effectors Research Articles

2'3'-cGAMP interactome identifies 2'3'-cGAMP/Rab18/FosB signaling in cell migration control independent of innate immunity.

c-di-GAMP was first identified in bacteria to promote colonization, while mammalian 2'3'-cGAMP is synthesized by cGAS to activate STING for innate immune stimulation. However, 2'3'-cGAMP function beyond innate immunity remains elusive. Here, we report that 2'3'-cGAMP promotes cell migration independent of innate immunity. 2'3'-cGAMP interactome analysis identifies the small GTPase Rab18 as a 2'3'-cGAMP binding partner and effector in cell migration control. Mechanistically, 2'3'-cGAMP binds Rab18 to facilitate GTP loading and subsequent Rab18 activation, which further promotes FosB transcription in facilitating cell migration. Induced synthesis of endogenous 2'3'-cGAMP by intrabreast tumor bacterium S. aureus infection or low-dose doxorubicin treatment facilitates cell migration depending on the cGAS/cGAMP/Rab18/FosB signaling. We find that lovastatin induces Rab18 deprenylation that abolishes 2'3'-cGAMP recognition therefore suppressing cell migration. Together, our study reveals a previously unidentified 2'3'-cGAMP function in cell migration control via the 2'3'-cGAMP/Rab18/FosB signaling that provides additional insights into clinical applications of 2'3'-cGAMP.

Toward Efficient Calculation of Inverses in Control Allocation for Safety-Critical Applications

Many control allocation algorithms require the calculation of (pseudo)inverses of control effectiveness matrices, also referred to as a B matrix, which for nonlinear systems might change over time. Such cases would require an online calculation of the respective inverses. Storage of all possible, offline precalculated inverses might exceed available memory sizes in common aircraft applications. This is especially relevant for systems with a high number of control effectors, like novel aircraft configurations. Several control allocation algorithms exist that require updates of the matrix to be inverted, the considered example being Redistributed Scaled Pseudoinverse. Within the Redistributed Scaled Pseudoinverse algorithm, the control allocation problem is solved iteratively by sequentially removing the columns of the B matrix that belong to saturated effectors. An approach using the Sherman–Morrison formula is presented in this study, which calculates the inverses based on recursive updates. This proposed approach has the following advantages over conventional Redistributed Scaled Pseudoinverse algorithm: reduced computational load and ease of protection against run-time errors. These make it a candidate for use in the context of safety-critical applications. The approach gives promising results and shows significant decrease of computational time. However, specific numerical challenges require additional investigations.

Control allocation optimization for an over-actuated tandem tiltwing eVTOL aircraft considering aerodynamic interactions

This paper describes control allocation strategies for a tandem tiltwing electric vertical take-off and landing (eVTOL) aircraft with distributed propulsion. The control mappings are constructed as local surrogate models that relate the control effectors to the aircraft's aeropropulsive forces and moments across the full flight envelope, including interactional aerodynamics effects. Control allocation optimization problems are formulated based on force and moment commands for specific flight conditions. Specifically, a nonlinear programming formulation based on nonlinear control mapping is proposed for control allocation optimization, and the problem is solved using a sparse nonlinear optimizer. The solutions obtained from different formulations such as the minimization of force and moment residuals and the minimization of control effort are investigated. Furthermore, these solutions are compared with the solutions obtained using linear control mapping-based formulations. Results presented for the cases of forward flight, low speed flight & hover, and flight in the transition corridor suggest that considering aerodynamic interactions while formulating and solving the control allocation problem is necessary for higher levels of accuracy compared to linear approaches. One-propeller-out scenarios and moment and force generation cases are also investigated. Finally, control allocation for steady and accelerated operation in the transition corridor is discussed. The contribution of the methods and results in the paper is a nonlinear control allocation methodology for the entire flight envelope of an over-actuated tandem tiltwing eVTOL aircraft.

Nonlinear dynamic inversion based full envelope robust flight control for coaxial compound helicopter

The flight control system of coaxial compound helicopters (CCHs) is a complex multi-variable system characterized by redundant control effectors, strong nonlinear characteristics, and multiple flight modes. This paper presents a unified robust control framework tailored for CCH full-envelope flight, utilizing nonlinear dynamic inversion and extended state observer techniques. The framework is specifically designed to tackle issues arising from a multi-mode nature, parametric uncertainties, and external disturbances. Within the unified framework, the study addresses inherent complexities such as nonlinearities and cross-coupling effects in CCH by leveraging nonlinear dynamic inversion to formulate flight control laws for both inner and outer-loops. To mitigate model uncertainties and external disturbances, the extended state observer is employed to estimate lumped disturbance effectively. Control allocation for both inner and outer-loops is devised to adapt to changes in control effector authorities and flight modes. Furthermore, an exponential control allocation strategy is proposed for the outer-loop to ensure a smooth pitch angle during transition flight. The effectiveness of the proposed control laws and control allocation strategies in achieving precise attitude tracking, transition flight and mission task elements (MTEs), even in the presence of notable model uncertainties and external disturbances, is demonstrated through numerical simulations.

Tumor Infiltrating Effector Regulatory T Cells Express VEGF Receptor 2 in Patients With Colorectal Cancer.

Regulatory T cells (Tregs) suppress various anti-tumor immune responses in the tumor microenvironment (TME) and their control is considered essential to enhancing efficacy of cancer immunotherapy. The purpose of the study was to evaluate the strategy to regulate Tregs through the vascular endothelial growth factor (VEGF) pathway. We evaluated VEGF receptor (VEGFR) expression in subtypes of Tregs by analysis of public databases and through flow cytometry by investigating surgically resected specimens and peripheral blood mononuclear cells (PBMCs) from 26 patients with advanced colorectal cancer (CRC). Analysis of The Cancer Genome Atlas colorectal adenocarcinoma dataset (n=592) showed that mRNA expression of both FLT1 (VEGFR1) and KDR (VEGFR2) was positively correlated with mRNA expression of FOXP3 as well as Treg signature. Clinical specimens revealed abundant VEGFR2 expression on Tregs, but very marginal VEGFR1 expression. The frequency of effector Tregs, the most immunosuppressive fraction of Tregs, was significantly higher in the tumor than in the PBMC and normal mucosa, and the majority of effector Tregs expressed VEGFR2. Furthermore, by using in vitro generated Tregs, the proportion of Tregs expressing IL-10 or TGF-β1 was significantly inhibited by a VEGFR2 inhibitor. A therapeutic strategy targeting the VEGFR2 axis may have a potential to control effector Tregs in the CRC-TME.

A Decentralized Voting and Monitoring Flight Control Actuation System for eVTOL Aircraft

The emergence of eVTOL (electrical Vertical Takeoff and Landing) aircraft necessitates the development of safe and efficient systems to meet stringent certification and operational requirements. The primary state-of-the-art technology for flight control actuation in eVTOL aircraft is electro-mechanical actuators (EMAs), which heavily rely on multiple redundancies of critical components to achieve fault tolerance. However, challenges persist in terms of insufficient reliability, immaturity, and a lack of a measurable evaluation method. This research addresses these issues by elucidating the design requirements for EMAs in eVTOL aircraft and proposing a systematic design and evaluation approach for EMA architecture. A key enhancement involves the incorporation of decentralized voting and monitoring (VoDeMo) mechanisms within the Electronic Control Units (ECUs) to improve the overall safety of the EMA. The paper introduces an innovative triple-dual redundant architecture for aircraft control effectors, comprising three dissimilar lanes of ECUs and two similar redundant parallel channels of power electronics and motors. The design is synergistically supported by a comprehensive evaluation that incorporates quantifiable Model-Based Safety Assessment (MBSA), utilizing both physical simulation and logical safety models. Hardware-In-the-Loop (HIL) tests are conducted on a constructed prototype to validate the proposed architecture.

Flight test of flying wing aircraft controlled by dual synthetic jets at Ma0.2

To explore the application potential of zero-mass-flux dual synthetic jets in flight control of flying wing aircraft (FWA), dual synthetic jet actuators (DSJAs) are integrated into a FWA and flight tests without deflections of rudders are firstly carried out to verify the viability of DSJAs to manipulate three-axis attitudes at a cruising speed of 70 m/s. Two active flow control methods of circulation control and reverse jet control performed by DSJAs are utilized to execute the three-axis control. Novel flight control effectors based on DSJAs are designed and achieve the integration with the FWA. Flight tests show that three-axis flight control is realized by DSJAs distributed in different locations. The maximum roll, pitch and yaw angular velocities are 10.12°/s, 6.17°/s and 8.38°/s respectively. The work initially verifies rudderless flight control ability of DSJAs at a cruising speed of 70 m/s and the control ability will be improved by the further optimization of DSJAs.

Spatiotemporal control of RNA metabolism and CRISPR-Cas functions using engineered photoswitchable RNA-binding proteins.

RNA molecules perform various crucial roles in diverse cellular processes, from translating genetic information to decoding the genome, regulating gene expression and catalyzing chemical reactions. RNA-binding proteins (RBPs) play an essential role in regulating the diverse behaviors and functions of RNA in live cells, but techniques for the spatiotemporal control of RBP activities and RNA functions are rarely reported yet highly desirable. We recently reported the development of LicV, a synthetic photoswitchable RBP that can bind to a specific RNA sequence in response to blue light irradiation. LicV has been used successfully for the optogenetic control of RNA localization, splicing, translation and stability, as well as for the photoswitchable regulation of transcription and genomic locus labeling. Compared to classical genetic or pharmacologic perturbations, LicV-based light-switchable effectors have the advantages of large dynamic range between dark and light conditions and submicron and millisecond spatiotemporal resolutions. In this protocol, we provide an easy, efficient and generalizable strategy for engineering photoswitchable RBPs for the spatiotemporal control of RNA metabolism. We also provide a detailed protocol for the conversion of a CRISPR-Cas system to optogenetic control. The protocols typically take 2-3 d, including transfection and results analysis. Most of this protocol is applicable to the development of novel LicV-based photoswitchable effectors for the optogenetic control of other RNA metabolisms and CRISPR-Cas functions.

System Identification of Unmanned Air Systems at Texas A&M University

This paper presents a summary of system identification flight testing and results for a variety of large and small fixed-wing and multirotor unmanned air systems at Texas A&M University from 1999 to 2023. The six different types of vehicles range from a large powered parafoil, to a fixed-wing vehicle with synthetic jet-actuated roll control effectors, to a radially asymmetric multirotor, to large and small fixed-wing vehicles, and to a Steppe eagle. The observer/Kalman filter identification algorithm is used to generate linear time-invariant state-space models, and the results for both near-real-time online model generation and postflight offline model generation are presented. The use and efficacy of a variety of test input types and their sensitivity to exogenous inputs such as turbulence, in addition to identified model evaluation and selection criteria, are discussed. Several generations of low size, weight, power, and cost flight-test instrumentation including the Developmental Flight-Test Instrumentation data acquisition package are also presented. Challenges that arose from the flight-testing campaigns along with solutions are highlighted in the paper.

Innovative Control Effectors for Maneuvering of Air Vehicles

Flow control is a rapidly developing key technological area which is subject to extensive research as it offers the potential to enhance aircraft aerodynamic performance, control, and maneuverability. The current paper details the methods and the results of a research which envisions assisting the newly formed NATO Task Group STO-AVT-239, with assessing the ability of modern active flow control actuators to improve the performance of Unmanned Combat Air Vehicles (UCAV). The project was supported by the ACE Undergraduate Research Topics Program at IIT and investigated the feasibility of the Coanda effect in achieving Circulation Control (CC) in order to produce rolling motion in cruise. Understanding of the performance of the SACCON airframe design and the complex vortex dominated flow field around was achieved through research papers and previous work of NATO Task Groups. It was discovered that a mid-span vortex influences and disturbs the flow above the control surfaces diminishing their effectiveness. A simple freeware computer code was used to predict the behavior of the airframe and the results were compared to experiment. The predictive abilities of the code were assessed to be good given the limitations of the software. Along with the airframe, CC was researched inorder to predict its maneuver control capabilities.The experimental data and the computationalpredictions were then used in combination witha semi-empirical aileron control model to predictthe aileron effectiveness and compare it tothe CC results. In order to be able to apply forresearch funding from appropriate institutions,a windtunnel experiment was designed andplanned to be conducted to validate the developedmodel.

Feasibility Investigation of Attitude Control with Shape Memory Alloy Actuator on a Tethered Wing

This study is aimed at assessing the feasibility of employing an innovative, smart-material-based control effector for an inflatable wing. A shape memory alloy (SMA) actuator is primarily investigated as a control effector in this work for its advantages of a simple actuation mechanism and a high force-to-weight ratio. This paper presents the design, control strategy and simulation results of the SMA actuator used as a stability augmentation system for a small-scale prototype kite. Stable flight of the kite is achieved during open wind tunnel tests using the SMA actuator. Based on experimental and simulation analyses, it is evident that the current SMA actuator is better for low-frequency actuations rather than stability augmentation purposes, as its performance is sensitive to practical conditions. The study also discusses potential improvements and applications of the SMA actuator.

Intrinsic STAT4 Expression Controls Effector CD4 T Cell Migration and Th17 Pathogenicity.

Effector CD4 T cells are central to the development of autoimmune chronic inflammatory diseases, yet factors that mediate pathogenicity remain ill-defined. Single-nucleotide polymorphisms in the human STAT4 locus are associated with susceptibility to multiple autoimmune disorders, and Stat4 is linked to the pathogenic Th17 gene signature; however, Th17 cells differentiate independently of STAT4. Hence the interplay between STAT4 and CD4 T cell function, especially Th17 cells, during autoimmune disease is unclear. In this article, we demonstrate that CD4 T cell-intrinsic STAT4 expression is essential for the induction of autoimmune CNS inflammation in mice, in part by regulating the migration of CD4 T cells to the inflamed CNS. Moreover, unbiased transcriptional profiling revealed that STAT4 controls the expression of >200 genes in Th17 cells and is important for the upregulation of genes associated with IL-23-stimulated, pathogenic Th17 cells. Importantly, we show that Th17 cells specifically require STAT4 to evoke autoimmune inflammation, highlighting, to our knowledge, a novel function for STAT4 in Th17 pathogenicity.

Natural effectors for conformational control of coronavirus spike proteins.

Sialic acid (Sia) at the cell surface is a putative SARS-CoV-2 co-receptor via interactions with Spike N-terminal domain (NTD), and Sia-based inhibitors have shown efficacy against SARS-CoV-2 in culture. However, protein:small-molecule complexes pose difficult cryo-EM targets because small ligands typically act in relatively poorly resolved peripheral regions, and structural details of Spike:Sia interactions via the highly flexible NTD remain elusive. Spike receptor-binding domain (RBD) binds linoleic acid (LA), which interacts with neighboring RBD to lock-in a closed trimer with rigid, well-resolved NTDs. While endogenous LA from certain expression systems serendipitously permits visualization of bound Sia, necessary and sufficient conditions for reliable extraction of this complex remain unclear.

Neural Decoding for Intracortical Brain-Computer Interfaces.

Brain-computer interfaces have revolutionized the field of neuroscience by providing a solution for paralyzed patients to control external devices and improve the quality of daily life. To accurately and stably control effectors, it is important for decoders to recognize an individual's motor intention from neural activity either by noninvasive or intracortical neural recording. Intracortical recording is an invasive way of measuring neural electrical activity with high temporal and spatial resolution. Herein, we review recent developments in neural signal decoding methods for intracortical brain-computer interfaces. These methods have achieved good performance in analyzing neural activity and controlling robots and prostheses in nonhuman primates and humans. For more complex paradigms in motor rehabilitation or other clinical applications, there remains more space for further improvements of decoders.

System Identification of a Subscale Distributed Electric Propulsion Aircraft

Flight testing of a 21%-scale Cirrus SR22T aircraft with a distributed electric propulsion system was performed with the goal of identifying the influence of distributed propulsion units on the aircraft flight dynamics. Stability and control derivatives for this configuration were identified for a linear aircraft model, including throttle-based control influences of a semispan-distributed array of propulsors. Unknown model parameters were identified from flight test data under unsteady excitation of control effectors using frequency-domain system-identification methods, and the resultant model was validated against independently acquired sets of flight data. The identified throttle-based control derivatives were characteristic of anticipated local thrust contributions from each propulsor and associated proportional yawing moments. Additional throttle-based control influences were also observed, through modulation in the aircraft lift, pitch, and roll characteristics. Furthermore, significant spanwise nonuniformity was observed in the aircraft lift sensitivity to throttle changes, which was linked to three-dimensional influences of the wing aerodynamics. These observations demonstrate the inherent degree of interconnectivity between aerodynamics, propulsion, and control subsystems characteristic of aircraft with distributed electric propulsion systems.

Med1 Controls Effector CD8+ T Cell Differentiation and Survival through C/EBPβ-Mediated Transcriptional Control of T-bet.

Effector CD8+ T cells are crucial players in adaptive immunity for effective protection against invading pathogens. The regulatory mechanisms underlying CD8+ T cell effector differentiation are incompletely understood. In this study, we defined a critical role of mediator complex subunit 1 (Med1) in controlling effector CD8+ T cell differentiation and survival during acute bacterial infection. Mice with Med1-deficient CD8+ T cells exhibited significantly impaired expansion with evidently reduced killer cell lectin-like receptor G1+ terminally differentiated and Ly6c+ effector cell populations. Moreover, Med1 deficiency led to enhanced cell apoptosis and expression of multiple inhibitory receptors (programmed cell death 1, T cell Ig and mucin domain-containing-3, and T cell immunoreceptor with Ig and ITIM domains). RNA-sequencing analysis revealed that T-bet- and Zeb2-mediated transcriptional programs were impaired in Med1-deficient CD8+ T cells. Overexpression of T-bet could rescue the differentiation and survival of Med1-deficient CD8+ effector T cells. Mechanistically, the transcription factor C/EBPβ promoted T-bet expression through interacting with Med1 in effector T cells. Collectively, our findings revealed a novel role of Med1 in regulating effector CD8+ T cell differentiation and survival in response to bacterial infection.

Trailing-edge jets for UCAV's flight control over a wide speed range

With fluidic control effectors, the flying-wing aircraft have been expected to achieve flapless fight which can reduce the radar cross section (RCS). However, most researches are focused on their control capability at low speed (Ma<0.3). This paper numerically investigates using trailing-edge jets (TE jets) to control a flying-wing UCAV over a wide speed range (Ma=0.145∼0.7) to evaluate 3-axis flight control capability, bleeding air impacts on engine performance, and stealth improvement. The three-dimensional flow is simulated by a Reynolds–averaged Navier–Stokes (RANS) solver with k−ω SST turbulence model. The power consumption of bleeding air is converted into additional drag, and the control efficiency factor is proposed to compare the efficiency of fluidic and solid control effectors under a unified framework. The RCS is evaluated by the Large Element Physical Optics (LEPO) solver. The results show that, for pitch and roll control, TE jets relying on circulation control (CC) can produce the same moment as control surfaces deflected 30°, 20°, and 10° at Ma=0.145,0.4, and 0.7, respectively. Meanwhile, TE jets have less effect on the engine mass flow and thrust, and are more efficient at producing control moments than control surfaces. For yaw control, relying on the recoil effect, TE jets' control capability is equal to that of split flaps at low speed with relatively higher bleeding air impacts on engine performance, but will not be affected by the flow separation at the high angle of attack. For stealth characteristics, the RCS of jet-controlled UCAV in frontal, lateral, and some specific azimuth ranges reduces remarkably. This study indicates that TE jets are highly promising pitch and roll control effectors for a flying-wing UCAV to enhance survivability from low speed to high subsonic speed.

How the Potassium Channel Response of T Lymphocytes to the Tumor Microenvironment Shapes Antitumor Immunity.

Simple SummaryIon channels are proteins that control the movement of ions across the membranes of cells, thus regulating their physiological functions. In T lymphocytes, ion channels control the Ca2+ influx that, in turn, promotes proliferation and effector functions. In the context of cancer, T cells have the role of fighting tumor cells. However, the tumor microenvironment negatively regulates T cell antitumor capabilities. Therefore, it is of utmost importance to understand the relationship between the tumor microenvironment and the ion channel apparatus of T cells to overcome the tumors’ immunosuppressive capabilities.Competent antitumor immune cells are fundamental for tumor surveillance and combating active cancers. Once established, tumors generate a tumor microenvironment (TME) consisting of complex cellular and metabolic elements that serve to suppress the function of antitumor immune cells. T lymphocytes are key cellular elements of the TME. In this review, we explore the role of ion channels, particularly K+ channels, in mediating the suppressive effects of the TME on T cells. First, we will review the complex network of ion channels that mediate Ca2+ influx and control effector functions in T cells. Then, we will discuss how multiple features of the TME influence the antitumor capabilities of T cells via ion channels. We will focus on hypoxia, adenosine, and ionic imbalances in the TME, as well as overexpression of programmed cell death ligand 1 by cancer cells that either suppress K+ channels in T cells and/or benefit from regulating these channels’ activity, ultimately shaping the immune response. Finally, we will review some of the cancer treatment implications related to ion channels. A better understanding of the effects of the TME on ion channels in T lymphocytes could promote the development of more effective immunotherapies, especially for resistant solid malignancies.

Load Alleviation of Flexible Aircraft by Dynamic Control Allocation

As wing designs aim for higher aerodynamic efficiency, the underlying aircraft structure becomes more flexible, requiring additional features to alleviate the loads encountered from gusts and maneuvers. While alleviating loads, it is desirable to minimize the deviations from the original flight trajectory. In this work, a dynamic control allocation method that exploits redundant control effectors for maneuver and gust load alleviation is proposed for flexible aircraft. The control architecture decouples the two objectives of load alleviation and rigid-body trajectory tracking by exploiting the null space between the input and the rigid-body output. A reduced-dimensional null space input is established, which affects the flexible output (but not the rigid-body output) when passed through a null space filter to generate incremental control signals. This null space input is determined by model predictive control to maintain the flexible output of the aircraft within specified values, thereby achieving load alleviation. Numerical simulations are used to illustrate the operation of this load alleviation system on nonlinear models. It is shown that the proposed load alleviation system can successfully avoid the violation of load bounds in the presence of both gust disturbances and maneuvers with minimal effect on the trajectory tracking performance.

Interleukin 21‐induced Mitochondrial Dysfunction Drives Regulatory T Cell Inflammatory Response during Intestinal Inflammation

BackgroundSignificant proportion of inflammatory bowel disease (IBD) patients continue to respond inconsistently to therapies, underscoring disease complexity and the need for efficacious treatment. Interleukin 21 (IL‐21), which is known to support T helper (Th) cell function, is highly expressed within inflamed intestinal tissues of IBD patients compared to healthy controls. In addition, inflammatory regulatory T cells (Tregs) have been linked to refractory human IBD. Given that healthy Tregs are critical for self‐tolerance and prevention of IBD, we investigated the metabolic role of IL‐21 in instigating Treg dysfunction and the therapeutic ramifications of targeting metabolism pathways during IBD pathogenesis.MethodsHuman Tregs as well as relevant control effector Th cells were generated from naïve CD4+ T cells isolated from healthy blood donors. Microarray analysis was utilized for targeted metabolic transcriptional profiling. Immune phenotyping was assessed by fluorescence‐activated cell sorting. Metabolic phenotyping of cells was assessed by Seahorse flux analysis and mass spectrometry‐based metabolomics. Ultrastructural analysis of mitochondria was performed by confocal and transmission electron microscopy. Intestinal inflammation was induced in Rag1‐/‐ (T and B cell deficient) mice by the adoptive transfer of pathogenic naïve CD4+ T cells.ResultsAcute IL‐21 stimulation of human Tregs induced glycolysis and fluctuations in mitochondrial respiration (i.e. oxidative phosphorylation – OXPHOS), as assessed by Seahorse flux analysis. In agreement, microarray analysis, validated by qPCR, revealed an IL‐21‐mediated increase in the expression of genes associated with glycolysis and pathways known to support anabolic and OXPHOS metabolism, thus resembling a hypermetabolic state. Furthermore, IL‐21 stimulation rendered Tregs susceptible to inflammatory response, as evidenced by the production of effector Th cell‐associated cytokines such as interferon γ, tumor necrosis factor, IL‐17A, and IL‐17F. Exploring the mechanisms underlying IL‐21‐induced effects, we found significant disruption of mitochondrial integrity with concomitant activation of glycogen synthase kinase 3 (GSK3) β, a kinase known to prevent pyruvate entry into the mitochondria. IL‐21‐induced GSK3β activation was accompanied by a marked increase in intracellular and extracellular metabolites such as pyruvate and lactate, as assessed by metabolomics. Importantly, GSK3 inhibition or supplementation with mitochondrial membrane‐permeable methyl pyruvate broadly abrogated metabolic wiring of and inflammatory responses by IL‐21‐stimulated Tregs and effector Th cells. Collectively, these results suggest that impaired mitochondrial pyruvate metabolism is a feature of inflammatory CD4+ T cells. Lastly, GSK3 inhibition prevented pathogenic CD4+ T cell‐induced colitis in mice as evidenced by reduced Disease Activity Index, Mouse Colon Histology Index, and serum inflammatory cytokines.ConclusionsIL‐21 potently engages human Tregs in a hypermetabolic state that augments inflammatory cytokine production via induction of mitochondrial dysfunction. Therefore desensitizing CD4+ T cells to detrimental cues, such as IL‐21, may also augment Treg function during human IBD.