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The cellular and molecular events that drive the early development of innate lymphoid cells (ILCs) remain poorly understood. We show that the transcription factor TCF-1 is required for the efficient generation of all known adult ILC subsets and their precursors. Using novel reporter mice, we identified a new subset of early ILC progenitors (EILPs) expressing high amounts of TCF-1. EILPs lacked efficient T and B lymphocyte potential but efficiently gave rise to NK cells and all known adult helper ILC lineages, indicating that they are the earliest ILC-committed progenitors identified so far. Our results suggest that upregulation of TCF-1 expression denotes the earliest stage of ILC fate specification. The discovery of EILPs provides a basis for deciphering additional signals that specify ILC fate.
Assuntos
Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Imunidade Inata , Linfócitos/citologia , Linfócitos/imunologia , Fator 1 de Transcrição de Linfócitos T/genética , Regulação para Cima , Animais , Células Cultivadas , Citometria de Fluxo , Camundongos , Análise em Microsséries , Fator 1 de Transcrição de Linfócitos T/metabolismoRESUMO
The chemisorption energy of reactants on a catalyst surface, [Formula: see text], is among the most informative characteristics of understanding and pinpointing the optimal catalyst. The intrinsic complexity of catalyst surfaces and chemisorption reactions presents significant difficulties in identifying the pivotal physical quantities determining [Formula: see text]. In response to this, the study proposes a methodology, the feature deletion experiment, based on Automatic Machine Learning (AutoML) for knowledge extraction from a high-throughput density functional theory (DFT) database. The study reveals that, for binary alloy surfaces, the local adsorption site geometric information is the primary physical quantity determining [Formula: see text], compared to the electronic and physiochemical properties of the catalyst alloys. By integrating the feature deletion experiment with instance-wise variable selection (INVASE), a neural network-based explainable AI (XAI) tool, we established the best-performing feature set containing 21 intrinsic, non-DFT computed properties, achieving an MAE of 0.23 eV across a periodic table-wide chemical space involving more than 1,600 types of alloys surfaces and 8,400 chemisorption reactions. This study demonstrates the stability, consistency, and potential of AutoML-based feature deletion experiment in developing concise, predictive, and theoretically meaningful models for complex chemical problems with minimal human intervention.
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CD4(+) follicular helper T cells (T(FH) cells) are essential for germinal center (GC) responses and long-lived antibody responses. Here we report that naive CD4(+) T cells deficient in the transcription factor Foxp1 'preferentially' differentiated into T(FH) cells, which resulted in substantially enhanced GC and antibody responses. We found that Foxp1 used both constitutive Foxp1A and Foxp1D induced by stimulation of the T cell antigen receptor (TCR) to inhibit the generation of T(FH) cells. Mechanistically, Foxp1 directly and negatively regulated interleukin 21 (IL-21); Foxp1 also dampened expression of the costimulatory molecule ICOS and its downstream signaling at early stages of T cell activation, which rendered Foxp1-deficient CD4(+) T cells partially resistant to blockade of the ICOS ligand (ICOSL) during T(FH) cell development. Our findings demonstrate that Foxp1 is a critical negative regulator of T(FH) cell differentiation.
Assuntos
Diferenciação Celular , Fatores de Transcrição Forkhead/fisiologia , Proteínas Repressoras/fisiologia , Linfócitos T Auxiliares-Indutores/citologia , Animais , Linfócitos T CD4-Positivos/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Interleucinas/genética , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T/fisiologiaRESUMO
In mammals, the most remarkable T cell variations with aging are the shrinking of the naïve T cell pool and the enlargement of the memory T cell pool, which are partially caused by thymic involution. However, the mechanism underlying the relationship between T-cell changes and aging remains unclear. In this study, we find that T-cell-specific Rip1 KO mice show similar age-related T cell changes and exhibit signs of accelerated aging-like phenotypes, including inflammation, multiple age-related diseases, and a shorter lifespan. Mechanistically, Rip1-deficient T cells undergo excessive apoptosis and promote chronic inflammation. Consistent with this, blocking apoptosis by co-deletion of Fadd in Rip1-deficient T cells significantly rescues lymphopenia, the imbalance between naïve and memory T cells, and aging-like phenotypes, and prolongs life span in T-cell-specific Rip1 KO mice. These results suggest that the reduction and hyperactivation of T cells can have a significant impact on organismal health and lifespan, underscoring the importance of maintaining T cell homeostasis for healthy aging and prevention or treatment of age-related diseases.
Assuntos
Senilidade Prematura , Linfócitos T , Animais , Camundongos , Envelhecimento/genética , Senilidade Prematura/genética , Apoptose , Inflamação , MamíferosRESUMO
BACKGROUND: Streptococcus suis is an important zoonotic pathogen. Biofilm formation largely explains the difficulty in preventing and controlling S. suis. However, little is known about the molecular mechanism of S. suis biofilm formation. RESULTS: In this study, transcriptomic and metabolomic analyses of S. suis in biofilm and planktonic states were performed to identify key genes and metabolites involved in biofilm formation. A total of 789 differential genes and 365 differential metabolites were identified. By integrating transcriptomics and metabolomics, five main metabolic pathways were identified, including amino acid pathway, nucleotide metabolism pathway, carbon metabolism pathway, vitamin and cofactor metabolism pathway, and aminoacyl-tRNA biosynthesis metabolic pathway. CONCLUSIONS: These results provide new insights for exploring the molecular mechanism of S. suis biofilm formation.
Assuntos
Biofilmes , Metabolômica , Streptococcus suis , Streptococcus suis/genética , Streptococcus suis/metabolismo , Biofilmes/crescimento & desenvolvimento , Redes e Vias Metabólicas/genética , Transcriptoma , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Metaboloma , MultiômicaRESUMO
Streptococcus suis is one of the major pathogens of pigs circulating worldwide, and the development of vaccines will help to effectively control streptococcosis in swine. In this study, we evaluated the potential of three membrane associated proteins, histidine kinase (HK), glycosyltransferase family 2 (Gtf-2) and phosphate binding protein (PsbP) of S. suis as subunit vaccines. Bioinformatics analysis shows that protein ABC is highly conserved in S. suis. To verify the protective effects of these proteins in animal models, recombinant protein HK, Gtf-2 and PsbP were used to immunize BALB/c mice separately. The results showed that these proteins immunization in mice can effectively induce strong humoral immune responses, protect mice from cytokine storms caused by S. suis infection, and have a significant protective effect against lethal doses of S. suis infection. Furthermore, antibodies with opsonic activity exist in the recombinant proteins antiserum to assist phagocytic cells in killing S. suis. Overall, these results indicated that these recombinant proteins all elicit good immune protective effect against S. suis infection and can be represent promising candidate antigens for subunit vaccines against S. suis.
Assuntos
Anticorpos Antibacterianos , Proteínas de Bactérias , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Proteínas Recombinantes , Infecções Estreptocócicas , Vacinas Estreptocócicas , Streptococcus suis , Vacinas de Subunidades Antigênicas , Streptococcus suis/imunologia , Streptococcus suis/genética , Animais , Infecções Estreptocócicas/prevenção & controle , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/microbiologia , Camundongos , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Proteínas de Bactérias/imunologia , Proteínas de Bactérias/genética , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/genética , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/genética , Vacinas Estreptocócicas/imunologia , Vacinas Estreptocócicas/administração & dosagem , Vacinas Estreptocócicas/genética , Sorogrupo , Citocinas/metabolismo , Feminino , Proteínas de Membrana/imunologia , Proteínas de Membrana/genética , Imunidade Humoral , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/genética , Doenças dos Suínos/prevenção & controle , Doenças dos Suínos/imunologia , Doenças dos Suínos/microbiologia , Suínos , Biologia ComputacionalRESUMO
Accurate estimates of fossil fuel CO2 (FFCO2) emissions are of great importance for climate prediction and mitigation regulations but remain a significant challenge for accounting methods relying on economic statistics and emission factors. In this study, we employed a regional data assimilation framework to assimilate in situ NO2 observations, allowing us to combine observation-constrained NOx emissions coemitted with FFCO2 and grid-specific CO2-to-NOx emission ratios to infer the daily FFCO2 emissions over China. The estimated national total for 2016 was 11.4 PgCO2·yr-1, with an uncertainty (1σ) of 1.5 PgCO2·yr-1 that accounted for errors associated with atmospheric transport, inversion framework parameters, and CO2-to-NOx emission ratios. Our findings indicated that widely used "bottom-up" emission inventories generally ignore numerous activity level statistics of FFCO2 related to energy industries and power plants in western China, whereas the inventories are significantly overestimated in developed regions and key urban areas owing to exaggerated emission factors and inexact spatial disaggregation. The optimized FFCO2 estimate exhibited more distinct seasonality with a significant increase in emissions in winter. These findings advance our understanding of the spatiotemporal regime of FFCO2 emissions in China.
Assuntos
Dióxido de Carbono , Monitoramento Ambiental , Combustíveis Fósseis , Dióxido de Nitrogênio , Dióxido de Carbono/análise , Poluentes Atmosféricos/análise , Monitoramento Ambiental/métodos , Dióxido de Nitrogênio/análise , Estações do AnoRESUMO
Long noncoding RNAs (lncRNAs) are a distinct subtype of RNA that lack protein-coding capacity but exert significant influence on various cellular processes. In non-small cell lung cancer (NSCLC), dysregulated lncRNAs act as either oncogenes or tumor suppressors, contributing to tumorigenesis and tumor progression. LncRNAs directly modulate gene expression, act as competitive endogenous RNAs by interacting with microRNAs or proteins, and associate with RNA binding proteins. Moreover, lncRNAs can reshape the tumor immune microenvironment and influence cellular metabolism, cancer cell stemness, and angiogenesis by engaging various signaling pathways. Notably, lncRNAs have shown great potential as diagnostic or prognostic biomarkers in liquid biopsies and therapeutic strategies for NSCLC. This comprehensive review elucidates the significant roles and diverse mechanisms of lncRNAs in NSCLC. Furthermore, we provide insights into the clinical relevance, current research progress, limitations, innovative research approaches, and future perspectives for targeting lncRNAs in NSCLC. By summarizing the existing knowledge and advancements, we aim to enhance the understanding of the pivotal roles played by lncRNAs in NSCLC and stimulate further research in this field. Ultimately, unraveling the complex network of lncRNA-mediated regulatory mechanisms in NSCLC could potentially lead to the development of novel diagnostic tools and therapeutic strategies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , MicroRNAs , RNA Longo não Codificante , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , MicroRNAs/genética , Oncogenes , Regulação Neoplásica da Expressão Gênica , Microambiente TumoralRESUMO
Immunotherapy has emerged to play a rapidly expanding role in the treatment of cancers. Currently, many clinical trials of therapeutic agents are on ongoing with majority of immune checkpoint inhibitors (ICIs) especially programmed death receptor 1 (PD-1) and its ligand 1 (PD-L1) inhibitors. PD-1 and PD-L1, two main immune checkpoints, are expressed at high levels in thymic epithelial tumors (TETs) and could be predictors of the progression and immunotherapeutic efficacy of TETs. However, despite inspiring efficacy reported in clinical trials and clinical practice, significantly higher incidence of immune-related adverse events (irAEs) than other tumors bring challenges to the administration of ICIs in TETs. To develop safe and effective immunotherapeutic patterns in TETs, understanding the clinical properties of patients, the cellular and molecular mechanisms of immunotherapy and irAEs occurrence are crucial. In this review, the progress of both basic and clinical research on immune checkpoints in TETs, the evidence of therapeutic efficacy and irAEs based on PD-1 /PD-L1 inhibitors in TETs treatment are discussed. Additionally, we highlighted the possible mechanisms underlying irAEs, prevention and management strategies, the insufficiency of current research and some worthy research insights. High PD-1/PD-L1 expression in TETs provides a rationale for ICI use. Completed clinical trials have shown an encouraging efficacy of ICIs, despite the high rate of irAEs. A deeper mechanism understanding at molecular level how ICIs function in TETs and why irAEs occur will help maximize the immunotherapeutic efficacy while minimizing irAEs risks in TET treatment to improve patient prognosis.
Assuntos
Neoplasias Epiteliais e Glandulares , Neoplasias do Timo , Humanos , Antígeno B7-H1 , Receptor de Morte Celular Programada 1 , Imunoterapia/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Epiteliais e Glandulares/tratamento farmacológicoRESUMO
The molecular mechanisms that underlie T cell quiescence are poorly understood. Here we report that mature naive CD8(+) T cells lacking the transcription factor Foxp1 gained effector phenotype and function and proliferated directly in response to interleukin 7 (IL-7) in vitro. Foxp1 repressed expression of the IL-7 receptor α-chain (IL-7Rα) by antagonizing Foxo1 and negatively regulated signaling by the kinases MEK and Erk. Acute deletion of Foxp1 induced naive T cells to gain an effector phenotype and proliferate in lympho-replete mice. Foxp1-deficient naive CD8(+) T cells proliferated even in lymphopenic mice deficient in major histocompatibility complex class I. Our results demonstrate that Foxp1 exerts essential cell-intrinsic regulation of naive T cell quiescence, providing direct evidence that lymphocyte quiescence is achieved through actively maintained mechanisms that include transcriptional regulation.
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Proliferação de Células , Fatores de Transcrição Forkhead/imunologia , Proteínas Repressoras/imunologia , Linfócitos T/imunologia , Animais , Butadienos/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Inibidores Enzimáticos/farmacologia , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/imunologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Citometria de Fluxo , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Imidazóis/farmacologia , Immunoblotting , Interleucina-7/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/imunologia , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Nitrilas/farmacologia , Ligação Proteica , Piridinas/farmacologia , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/imunologia , Receptores de Interleucina-7/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismoRESUMO
Streptococcus suis (S. suis) regulates biofilm formation through LuxS/AI-2 quorum sensing system, increasing drug resistance and exacerbating infection. The anti-hyperglycaemic agent metformin has anti-bacterial and anti-biofilm activities. This study aimed to investigate the anti-biofilm and anti-quorum sensing activity of metformin in S. suis. We first determined the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of metformin on S. suis. The results indicated that metformin showed no obvious inhibitory or bactericidal effect. Crystal violet staining showed that metformin significantly inhibited the formation of S. suis biofilm at sub-MIC concentration, which was also confirmed by scanning electron microscopy. Then, we quantified the AI-2 signal molecules in S. suis, and the results showed that metformin had a significant inhibitory effect on the production of AI-2 signal in S. suis. Inhibition of enzyme activity and molecular docking experiments showed that metformin has a significant binding activity to LuxS protein. In addition, qRT-PCR results showed that metformin significantly down-regulated the expression of AI-2 synthesis-related genes luxS and pfs, and adhesion-related genes luxS, pfs, gapdh, sly, fbps, and ef. Western blotting also showed that metformin significantly reduced the expression of LuxS protein. Our study suggests that metformin seems to be a suitable candidate for the inhibition of S. suis LuxS/AI-2 QS system and prevention of biofilm formation, which provided a new idea for the prevention and control of S. suis.
Assuntos
Streptococcus suis , Streptococcus suis/metabolismo , Simulação de Acoplamento Molecular , Homosserina/metabolismo , Proteínas de Bactérias/metabolismo , Percepção de Quorum , Biofilmes , Liases de Carbono-Enxofre/genética , Liases de Carbono-Enxofre/metabolismo , Liases de Carbono-Enxofre/farmacologia , Lactonas/metabolismoRESUMO
BACKGROUND: The scavenger receptor CD36 was reported to be highly expressed on tumor-infiltrating CD8+ T cells, but the clinical role remains obscure. This study aims to explore the infiltration and clinical value of CD36+CD8+ T cells in NSCLC. METHODS: Immunohistochemistry and immunofluorescence were conducted for survival analyses and immunological evaluation in 232 NSCLC patients in Zhongshan Hospital. Flow cytometry analyses were carried out to assess the immune cells from fresh tumor samples, non-tumor tissues and peripheral blood. In vitro tumor infiltrating lymphocytes cultures were conducted to test the effect of CD36 blockage. RESULTS: Accumulation of CD36+CD8+ T cells in tumor tissues was correlated with more advanced stage (p < 0.001), larger tumor size (p < 0.01), and lymph node metastasis (p < 0.0001) in NSCLC. Moreover, high infiltration of CD36+CD8+ T cells indicated poor prognosis in terms of both overall survival (OS) and recurrence-free survival (RFS) and inferior chemotherapy response. CD36+CD8+ T cells showed decreased GZMB (p < 0.0001) and IFN-γ (p < 0.001) with elevated PD-1 (p < 0.0001) and TIGIT (p < 0.0001). Analysis of tumor-infiltrating immune cell landscape revealed a positive correlation between CD36+CD8+ T cells and Tregs (p < 0.01) and M2-polarized macrophages (p < 0.01) but a negative correlation with Th1 (p < 0.05). Notably, inhibition of CD36 partially restored the cytotoxic function of CD8+ T cells by producing more GZMB and IFN-γ. CONCLUSION: CD36+CD8+ T cells exhibit impaired immune function and high infiltration of CD36+CD8+ T cells indicated poor prognosis and inferior chemotherapy response in NSCLC patients. CD36 could be a therapeutic target in combination with chemotherapy in NSCLC patients.
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Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Linfócitos do Interstício Tumoral , Microambiente Tumoral , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Prognóstico , Microambiente Tumoral/imunologia , Antígenos CD36/imunologiaRESUMO
In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy, but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown. In the case of Barrett's oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells. On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett's oesophagus in terms of the presence of intestinal goblet cells. Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63+KRT5+KRT7+) at the squamous-columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous-columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett's metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett's oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63+KRT5+KRT7+ basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett's oesophagus.
Assuntos
Esôfago de Barrett/patologia , Linhagem da Célula , Células Epiteliais/patologia , Epitélio/patologia , Junção Esofagogástrica/patologia , Células-Tronco/patologia , Animais , Esôfago de Barrett/genética , Esôfago de Barrett/metabolismo , Fator de Transcrição CDX2/genética , Fator de Transcrição CDX2/metabolismo , Rastreamento de Células , Esofagite/metabolismo , Esofagite/patologia , Junção Esofagogástrica/metabolismo , Refluxo Gastroesofágico , Células Caliciformes/metabolismo , Células Caliciformes/patologia , Humanos , Queratina-5/metabolismo , Queratina-7/metabolismo , Metaplasia/metabolismo , Metaplasia/patologia , Camundongos , Fosfoproteínas/metabolismo , Células-Tronco/metabolismo , Transativadores/metabolismoRESUMO
China started to implement comprehensive measures to mitigate traffic pollution at the end of 1990s, but the comprehensive effects, especially on ambient air quality and public health, have not yet been systematically evaluated. In this study, we analyze the effects of vehicle emission control measures on ambient air pollution and associated deaths attributable to long-term exposures of fine particulate matter (PM2.5) and O3 based on an integrated research framework that combines scenario analysis, air quality modeling, and population health risk assessment. We find that the total impact of these control measures was substantial. Vehicular emissions during 1998-2015 would have been 2-3 times as large as they actually were, had those measures not been implemented. The national population-weighted annual average concentrations of PM2.5 and O3 in 2015 would have been higher by 11.7 µg/m3 and 8.3 parts per billion, respectively, and the number of deaths attributable to 2015 air pollution would have been higher by 510 thousand (95% confidence interval: 360 thousand to 730 thousand) without these controls. Our analysis shows a concentration of mortality impacts in densely populated urban areas, motivating local policymakers to design stringent vehicle emission control policies. The results imply that vehicle emission control will require policy designs that are more multifaceted than traditional controls, primarily represented by the strict emission standards, with careful consideration of the challenges in coordinated mitigation of both PM2.5 and O3 in different regions, to sustain improvement in air quality and public health given continuing swift growth in China's vehicle population.
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Poluentes Atmosféricos/química , Poluição do Ar/prevenção & controle , Ozônio , Material Particulado , Meios de Transporte , Emissões de Veículos/análise , China , Exposição Ambiental/prevenção & controle , Monitoramento Ambiental/métodos , Humanos , Medição de RiscoRESUMO
Regulatory T (Treg) cells play central roles in maintaining immune homeostasis and self-tolerance. However, the molecular mechanisms underlying Treg cell homeostasis and suppressive function are still not fully understood. Here, we report that the deletion of another P subfamily members of the forkhead box (Foxp) subfamily member Foxp1 in Treg cells led to increased numbers of activated Treg (aTreg) cells at the expense of quiescent Treg cells, and also resulted in impaired Treg suppressive function. Mice with Foxp1-deficient Treg cells developed spontaneous inflammatory disease with age; they also had more severe inflammatory disease in colitis and experimental autoimmune encephalomyelitis (EAE) models. Mechanistically, we found that Foxp1 bound to the conserved noncoding sequence 2 (CNS2) element of the Foxp3 locus and helped maintain Treg suppressive function by stabilizing the Foxp3 expression. Furthermore, we found that Foxp1 and Foxp3 coordinated the regulation of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) expression levels. Taken together, our study demonstrates that Foxp1 plays critical roles in both maintaining Treg cell quiescence during homeostasis and regulating Treg suppressive function.
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Fatores de Transcrição Forkhead/metabolismo , Homeostase , Proteínas Repressoras/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Antígeno CTLA-4/metabolismo , Diferenciação Celular , Células HEK293 , Humanos , Ativação Linfocitária/imunologia , Camundongos Transgênicos , Transcrição GênicaRESUMO
Dendritic cells (DCs) play pivotal roles in T-cell homeostasis and activation, and metabolic programing has been recently linked to DC development and function. However, the metabolic underpinnings corresponding to distinct DC functions remain largely unresolved. Here, we demonstrate a special metabolic-epigenetic coupling mechanism orchestrated by tuberous sclerosis complex subunit 1 (TSC1)-mechanistic target of rapamycin (mTOR) for homeostatic DC function. Specific ablation of Tsc1 in the DC compartment (Tsc1DC-KO) largely preserved DC development but led to pronounced reduction in naïve and memory-phenotype cluster of differentiation (CD)8+ T cells, a defect fully rescued by concomitant ablation of mTor or regulatory associated protein of MTOR, complex 1 (Rptor) in DCs. Moreover, Tsc1DC-KO mice were unable to launch efficient antigen-specific CD8+ T effector responses required for containing Listeria monocytogenes and B16 melanomas. Mechanistically, our data suggest that the steady-state DCs tend to tune down de novo fatty acid synthesis and divert acetyl-coenzyme A (acetyl-CoA) for histone acetylation, a process critically controlled by TSC1-mTOR. Correspondingly, TSC1 deficiency elevated acetyl-CoA carboxylase 1 (ACC1) expression and fatty acid synthesis, leading to impaired epigenetic imprinting on selective genes such as major histocompatibility complex (MHC)-I and interleukin (IL)-7. Remarkably, tempering ACC1 activity was able to divert cytosolic acetyl-CoA for histone acetylation and restore the gene expression program compromised by TSC1 deficiency. Taken together, our results uncover a crucial role for TSC1-mTOR in metabolic programing of the homeostatic DCs for T-cell homeostasis and implicate metabolic-coupled epigenetic imprinting as a paradigm for DC specification.
Assuntos
Linfócitos T CD8-Positivos/metabolismo , Células Dendríticas/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo , Animais , Antígenos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/fisiologia , Células Dendríticas/imunologia , Epigênese Genética , Homeostase , Listeria monocytogenes , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/imunologia , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/imunologia , Proteínas Supressoras de Tumor/genéticaRESUMO
The host immune response is a fundamental mechanism for attenuating cancer progression. Here we report a role for the DNA demethylase and tumor suppressor TET2 in host anti-tumor immunity. Deletion of Tet2 in mice elevates IL-6 levels upon tumor challenge. Elevated IL-6 stimulates immunosuppressive granulocytic myeloid-derived suppressor cells (G-MDSCs), which in turn reduce CD8+ T cells upon tumor challenge. Consequently, systematic knockout of Tet2 in mice leads to accelerated syngeneic tumor growth, which is constrained by anti-PD-1 blockade. Removal of G-MDSCs by the anti-mouse Ly6g antibodies restores CD8+ T-cell numbers in Tet2-/- mice and reboots their anti-tumor activity. Importantly, anti-IL-6 antibody treatment blocks the expansion of G-MDSCs and inhibits syngeneic tumor growth. Collectively, these findings reveal a TET2-mediated IL-6/G-MDSCs/CD8+ T-cell immune response cascade that safeguards host adaptive anti-tumor immunity, offering a cell non-autonomous mechanism of TET2 for tumor suppression.
Assuntos
Células Supressoras Mieloides , Neoplasias , Imunidade Adaptativa , Animais , Linfócitos T CD8-Positivos , Contagem de Células , Proteínas de Ligação a DNA/genética , Dioxigenases , Camundongos , Neoplasias/genética , Proteínas Proto-Oncogênicas/genéticaRESUMO
BACKGROUND: To investigate the sensitivity and specificity of corneal confocal microscopy (CCM) in the diagnosis of immune-related motor neuron disease syndrome and evaluation of the response to immunosuppressive therapy. METHODS: Seventy-two patients with clinical manifestations of motor neuron disease (MND) were analysed. According to whether they had concomitant rheumatic immune disease or rheumatic immune antibody abnormalities, they were divided into an MND group (33 patients) and an immune-related MND syndrome group (39 patients). Another 10 healthy adults were selected as the control group. All individuals were examined by CCM. RESULTS: For Langerhans cell(LC) density, the area under the receiver operating characteristic(ROC)curve was 0.8, the best cut-off was 67.7 cells/mm2, the sensitivity was 79.5%, and the specificity was 72.7%. For inferior whorl length (IWL), the area under the ROC curve was 0.674, the best cut-off was 17.41 mm/mm2, the sensitivity was 69.2%, and the specificity was 66.7%. After immunosuppressive therapy in 5 patients with immune-related MND syndrome, the LCD was significantly reduced (P < 0.05), and there was no statistically significant change in the IWL (P > 0.05). CONCLUSION: The LC density and IWL are ideal for distinguishing MND from immune-related MND syndrome. The LC density reflects the immunotherapy response sensitively.
Assuntos
Neuropatias Diabéticas , Doença dos Neurônios Motores , Adulto , Córnea , Neuropatias Diabéticas/diagnóstico , Humanos , Microscopia Confocal , Doença dos Neurônios Motores/diagnóstico por imagem , Curva ROC , SíndromeRESUMO
Secretory Ig A (sIgA) plays an important role in the maintenance of intestinal homeostasis via cross-talk with gut microbiota. The defects in sIgA production could elicit dysbiosis of commensal microbiota and subsequently facilitate the development of inflammatory bowel disease. Our previous study revealed activating transcription factor 3 (ATF3) as an important regulator of follicular helper T (TFH) cells in gut. ATF3 deficiency in CD4+ T cells impaired the development of gut TFH cells, and therefore diminished sIgA production, which increased the susceptibility to murine colitis. However, the potential role of microbiota in ATF3-mediated gut homeostasis remains incompletely understood. In this study, we report that both Atf3-/- and CD4creAtf3fl/fl mice displayed profound dysbiosis of gut microbiota when compared with their littermate controls. The proinflammatory Prevotella taxa, especially Prevotella copri, were more abundant in ATF3-deficient mice when compared with littermate controls. This phenotype was obviously abrogated by adoptive transfer of either TFH cells or IgA+ B cells. Importantly, depletion of gut microbiota dramatically alleviated the severity of colitis in Atf3-/- mice, whereas transfer of microbiota from Atf3-/- mice to wild-type recipients increased their susceptibility to colitis. Collectively, these observations indicate the importance of IgA-microbiota interaction in ATF3-mediated gut homeostasis.
Assuntos
Fator 3 Ativador da Transcrição/imunologia , Linfócitos B/imunologia , Microbioma Gastrointestinal/imunologia , Homeostase/imunologia , Imunoglobulina A/imunologia , Células T Auxiliares Foliculares/imunologia , Fator 3 Ativador da Transcrição/genética , Animais , Disbiose/genética , Disbiose/imunologia , Disbiose/microbiologia , Homeostase/genética , Imunoglobulina A/genética , Camundongos , Camundongos Knockout , Prevotella/imunologiaRESUMO
Realizing the goal of the Paris Agreement to limit global warming to 2 °C by the end of this century will most likely require deployment of carbon-negative technologies. It is particularly important that China, as the world's top carbon emitter, avoids being locked into carbon-intensive, coal-fired power-generation technologies and undertakes a smooth transition from high- to negative-carbon electricity production. We focus here on deploying a combination of coal and biomass energy to produce electricity in China using an integrated gasification cycle system combined with carbon capture and storage (CBECCS). Such a system will also reduce air pollutant emissions, thus contributing to China's near-term goal of improving air quality. We evaluate the bus-bar electricity-generation prices for CBECCS with mixing ratios of crop residues varying from 0 to 100%, as well as associated costs for carbon mitigation and cobenefits for air quality. We find that CBECCS systems employing a crop residue ratio of 35% could produce electricity with net-zero life-cycle emissions of greenhouse gases, with a levelized cost of electricity of no more than 9.2 US cents per kilowatt hour. A carbon price of approximately $52.0 per ton would make CBECCS cost-competitive with pulverized coal power plants. Therefore, our results provide critical insights for designing a CBECCS strategy in China to harness near-term air-quality cobenefits while laying the foundation for achieving negative carbon emissions in the long run.