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Regulatory T cells (Tregs) are instrumental in maintaining immune tolerance and preventing destructive autoimmunity, but how heterogeneous Treg populations are established remains largely unknown. Here, we show that Zfp335 deletion in Tregs failed to differentiate into effector Tregs (eTregs) and lose Treg-suppressive function and that KO mice exhibited early-onset lethal autoimmune inflammation with unrestricted activation of conventional T cells. Single-cell RNASeq analyses revealed that Zfp335-deficient Tregs lacked a eTreg population and showed dramatic accumulation of a dysfunctional Treg subset. Mechanistically, Zfp335-deficient Tregs displayed reduced oxidative phosphorylation and dysfunctional mitochondrial activity. Further studies revealed that Zfp335 controlled eTreg differentiation by regulating fatty acid oxidation (FAO) through direct targeting of the FAO enzyme Hadha. Importantly, we demonstrate a positive correlation between ZNF335 and HADHA expression in human eTregs. Our findings reveal that Zfp335 controls FAO-driven eTreg differentiation to establish immune tolerance., Introduction Regulatory T cells (Tregs) expressing forkhead box P3 (Foxp3) play a key role in the establishment and maintenance of peripheral immune tolerance through the prevention and suppression of autoimmunity [...]

Curcumin (CUR) is a natural compound extracted from turmeric (Curcuma longa), which has been reported to be a promising anti-cancer drug in various cancers. However, poor water solubility and low bioavailability posed a challenge for clinical application of curcumin. In this work, four CUR prodrugs, namely PEG4000-SS-CUR, PEG1500-SS-CUR, PEG4000-SeSe-CUR and PEG1500-SeSe-CUR were synthesized. These four CUR prodrugs have high CUR loading content and can self-assemble into spherical nanoparticles (NPs) with particle size of 90–190 nm in aqueous solution. The four CUR prodrug NPs exhibit good colloidal stability in PBS buffer and promoted drug release in response to GSH. Due to the enhanced water solubility, the four CUR prodrug NPs all exhibit reduced cellular uptake amount as compared to CUR in in vitro cellular uptake study. The four CUR prodrug NPs exhibit similar cytotoxicity against 22Rv1 cells as compared to free CUR while PEG4000-SeSe-CUR NPs exhibit the highest cytotoxicity and induce the highest cell apoptosis ratio against 4T1 cells in in vitro antitumor effect study. PEG4000-SeSe-CUR NPs developed in this work were proven to be an effective nanoformulation of CUR against 4T1 cells. [ABSTRACT FROM AUTHOR]

Activation of cuproptosis pathway has been reported to hold great potential in the application of tumor treatment. But the efficacy of cuproptosis seriously limited by the insufficient accumulation in the tumor sites. Therefore, herein based on the strong stabilization effects of the metalloid element selenium (Se) on copper (Cu), a photothermic Cu2‐xSe nanoparticle encapsulated with bioresponsive dimethyl maleic anhydride (DMMA@Cu2‐xSe) as a copper‐carrier to improve the copper accumulation in tumor is constructed, thus achieving cuproptosis‐driven enhancement of thermotherapy. This nanosystem exhibits the enhancement of tumor cellular uptake by a weak acid‐triggered charge‐switching ability. Next step, the exposed Cu2‐xSe is oxidized and releases divalent copper by high‐level oxide. Then, the abundant copper induces more dihydrolipoamide S‐acetyltransferase oligomerization to down‐regulate FDX1 and tricarboxylic acid cycle‐related proteins, which leads to inhibiting aerobic respiration. Cuproptosis‐induced mitochondrial damage further improves thermotherapy by up‐regulating reactive oxygen species (ROS). In addition, the generated ROS also promotes copper release to strengthen cuproptosis, and eventually improves tumor thermotherapy in turn. In general, DMMA@Cu2‐xSe with sequentially triggered copper‐release, efficient cuproptosis, and appropriate photothermal is a self‐enhanced nanoplatform for cuproptosis‐driven enhancement of thermotherapy. [ABSTRACT FROM AUTHOR]

Early T‐cell development from CD4− CD8− double‐negative (DN) stage to CD4+ CD8+ double‐positive (DP) stage in the thymus is regulated through multiple steps involving a batch of sequentially expressed factors. Our preliminary data and a recent report showed that AT‐rich interaction domain 1A (Arid1a) is required for the transition from DN to DP stages, but the mechanism is not fully understood. In this study, we consolidated that conditional deletion of Arid1a in T‐cell lineage intrinsically caused developmental blocks from DN3 to DN4 stages, as well as from DN4 to DP stages using both in vivo adoptive T‐cell transfer model and in vitro culture system. The expression of intracellular TCRβ is significantly decreased in Arid1a‐deficient DN4 cells compared with WT cells. OT1 transgenic TCR can rescue the defect in the transition from DN3 to DN4 stages, but not from DN to DP stages. Furthermore, we observed a comparable or stronger proliferation capacity accompanied by a significant increase in cell death in Arid1a−/− DP cells compared with that in WT controls. RNA‐Seq analysis shows a significant enrichment of apoptotic pathway within differentially expressed genes between Arid1a−/− and WT DP cells, including the upregulation of Bim, Casp3 and Trp53 and the downregulation of Rorc, Bcl‐XL and Mcl1. Therefore, our study reveals a novel mechanism that Arid1a controls early T‐cell development by maintaining intracellular TCRβ expression‐mediated β‐selection and activating parallel cell survival pathways. [ABSTRACT FROM AUTHOR]

What is known and objective: Alpha‐lipoic acid (ALA) is widely used as a dietary supplement and antiageing agent. Insulin autoimmune syndrome (IAS) is the most serious adverse reaction reported with the use of ALA. The purpose of this study was to explore the clinical characteristics of ALA‐induced IAS and provide a scientific reference for clinical diagnosis, treatment and prevention. Methods: We collected literature on IAS cases induced by ALA for retrospective analysis in Chinese and English. Results and discussion: The median age of 37 patients (28 females and 9 males) was 61 years (range 32–82). The symptoms occurred at night and in the early morning (60.7%), in the late postprandial period (50.0%) or after fasting (35.7%), within hours in some patients and up to 2 months in others after stopping ALA or during medication treatment. Autonomic nervous system symptoms (81.1%) and neurological hypoglycaemia (64.9%) are the main clinical manifestations of hypoglycaemia. The blood glucose concentration at the onset of hypoglycaemia was 2.19 mmol/L (median, range 1.09–3.52), the insulin concentration was ≥100 μIU/ml (94.6%), and the C‐peptide concentration was ≤20 ng/ml (83.3%). Testing for IgG insulin autoantibodies (IAAs) was positive in 37 patients. Pancreatic imaging was unremarkable on computed tomography (CT), magnetic resonance imaging (MRI) and abdominal sonography. Hypoglycaemia disappeared within 5 days to 8 months after withdrawing ALA alone or using corticosteroid treatment. IAA turned negative in 7 months (median; range 2–36). Follow‐up showed no recurrent hypoglycaemic episodes at 7.25 months (median; range 1–36). What is new and conclusion: ALA‐induced IAS is a clinically rare autoimmune disease with hypoglycaemia that occurs during medication treatment or after drug withdrawal that should be treated promptly. [ABSTRACT FROM AUTHOR]

The migration is the key step for thymic T cells to enter circulation and then lymph nodes (LNs), essential for future immune surveillance. Although promoter-based transcriptional regulation through Foxo1, Klf2, Ccr7, and Sell regulates T-cell migration, it remains largely unexplored whether and how enhancers are involved in this process. Here we found that the conditional deletion of Med1, a component of the mediator complex and a mediator between enhancers and RNA polymerase II, caused a reduction of both CD4 + and CD8 + T cells in LNs, as well as a decrease of CD8 + T cells in the spleen. Importantly, Med1 deletion hindered the migration of thymic αβT cells into the circulation and then into LNs, accompanied by the downregulation of KLF2, CCR7, and CD62L. Mechanistically, Med1 promotes Klf2 transcription by facilitating Foxo1 binding to the Klf2 enhancer. Furthermore, forced expression of Klf2 rescued Ccr7 and Sell expression, as well as αβT-cell migration into LNs. Collectively, our study unveils a crucial role for Med1 in regulating the enhancer-based Foxo1-Klf2 transcriptional program and the migration of αβT cells into LNs, providing valuable insights into the molecular mechanisms underlying T-cell migration., (© 2024 Wiley‐VCH GmbH.)

CD8 + T cell immune responses are regulated by multi-layer networks, while the post-translational regulation remains largely unknown. Transmembrane ectodomain shedding is an important post-translational process orchestrating receptor expression and signal transduction through proteolytic cleavage of membrane proteins. Here, by targeting the sheddase A Disintegrin and Metalloprotease (ADAM)17, we defined a post-translational regulatory mechanism mediated by the ectodomain shedding in CD8 + T cells. Transcriptomic and proteomic analysis revealed the involvement of post-translational regulation in CD8 + T cells. T cell-specific deletion of ADAM17 led to a dramatic increase in effector CD8 + T cell differentiation and enhanced cytolytic effects to eliminate pathogens and tumors. Mechanistically, ADAM17 regulated CD8 + T cells through cleavage of membrane CD122. ADAM17 inhibition led to elevated CD122 expression and enhanced response to IL-2 and IL-15 stimulation in both mouse and human CD8 + T cells. Intriguingly, inhibition of ADAM17 in CD8 + T cells improved the efficacy of chimeric antigen receptor (CAR) T cells in solid tumors. Our findings reveal a critical post-translational regulation in CD8 + T cells, providing a potential therapeutic strategy of targeting ADAM17 for effective anti-tumor immunity., (© 2024. The Author(s).)

Memory CD8 + T cells play an essential role in providing effective and lifelong protection against pathogens. Comprehensive transcriptional and epigenetic networks are involved in modulating memory T cell development, but the molecular regulations of CD8 + memory T cell formation and long-term persistence remain largely unknown. In this study, we show that zinc finger protein 335 (Zfp335) is indispensable for CD8 + T cell memory establishment and maintenance during acute infections. Mice with Zfp335 deletion in CD8 + T cells exhibit a significant reduction of memory T cells and memory precursor cells in the contraction phase. Zfp335 deficiency in CD8 + T cells resulted in decreased expression of memory featured genes Eomes and IL-2Rβ, leading to a loss of memory identity and an increase of apoptosis in response to IL-7 and IL-15. Mechanistically, Zfp335 directly binds to and regulates TCF-1, known to be critical for memory T cell development. Importantly, overexpression TCF-1 could rescue the defects in the survival of both CD8 + memory precursors and memory T cells caused by Zfp335 deficiency. Collectively, our findings reveal that Zfp335 serves as a novel transcriptional factor upstream of TCF-1 in regulating CD8 + T cell memory., (Copyright © 2022 by The American Association of Immunologists, Inc.)

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., (Copyright © 2022 by The American Association of Immunologists, Inc.)