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Taurine is used to bolster immunity, but its effects on antitumor immunity are unclear. Here, we report that cancer-related taurine consumption causes T cell exhaustion and tumor progression. The taurine transporter SLC6A6 is correlated with aggressiveness and poor outcomes in multiple cancers. SLC6A6-mediated taurine uptake promotes the malignant behaviors of tumor cells but also increases the survival and effector function of CD8+ T cells. Tumor cells outcompete CD8+ T cells for taurine by overexpressing SLC6A6, which induces T cell death and malfunction, thereby fueling tumor progression. Mechanistically, taurine deficiency in CD8+ T cells increases ER stress, promoting ATF4 transcription in a PERK-JAK1-STAT3 signaling-dependent manner. Increased ATF4 transactivates multiple immune checkpoint genes and induces T cell exhaustion. In gastric cancer, we identify a chemotherapy-induced SP1-SLC6A6 regulatory axis. Our findings suggest that tumoral-SLC6A6-mediated taurine deficiency promotes immune evasion and that taurine supplementation reinvigorates exhausted CD8+ T cells and increases the efficacy of cancer therapies.
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Linfocitos T CD8-positivos , Glicoproteínas de Membrana , Taurina , Taurina/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Animales , Humanos , Ratones , Línea Celular Tumoral , Ratones Endogámicos C57BL , Estrés del Retículo Endoplásmico , Factor de Transcripción Activador 4/metabolismo , Transducción de Señal , Femenino , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Factor de Transcripción STAT3/metabolismoRESUMEN
Ag-specific effector CD4+ T cells play a crucial role in defending against exogenous pathogens. However, the mechanisms governing the differentiation and function of IFN-γ-producing effector CD4+ Th1 cells in immune responses remain largely unknown. In this study, we elucidated the pivotal role of zinc finger protein 335 (Zfp335) in regulating effector Th1 cell differentiation and survival during acute bacterial infection. Mice with Zfp335 knockout in OT-II cells exhibited impaired Ag-specific CD4+ T cell expansion accompanied by a significant reduction in resistance to Listeria infection. Furthermore, Zfp335 deficiency restricted the effector CD4+ Th1 cell population and compromised their survival upon Listeria challenge. The expression of T-bet and IFN-γ was accordingly decreased in Zfp335-deficient Th1 cells. Mechanistically, Zfp335 directly bound to the promoter region of the Lmna gene and regulated its expression. Overexpression of Lmna was able to rescue the survival and function of Zfp335-deficient effector Th1 cells. Therefore, our study provides novel insights into the mechanisms governing effector Th1 cell differentiation and survival during acute infection.
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Diferenciación Celular , Proteínas de Unión al ADN , Lamina Tipo A , Ratones Noqueados , Células TH1 , Factores de Transcripción , Animales , Ratones , Diferenciación Celular/inmunología , Diferenciación Celular/genética , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/inmunología , Interferón gamma/inmunología , Interferón gamma/metabolismo , Lamina Tipo A/genética , Listeriosis/inmunología , Ratones Endogámicos C57BL , Células TH1/inmunología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
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 αßT 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 αßT-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 αßT cells into LNs, providing valuable insights into the molecular mechanisms underlying T-cell migration.
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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/EBPß 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.
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Linfocitos T CD8-positivos , Subunidad 1 del Complejo Mediador , Animales , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Diferenciación Celular , Subunidad 1 del Complejo Mediador/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Mucinas/metabolismo , ARN/metabolismo , Receptores Similares a Lectina de Células NK/metabolismo , Proteínas de Dominio T Box/metabolismoRESUMEN
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-2Rß, 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.
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Linfocitos T CD8-positivos , Interleucina-15 , Animales , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/genética , Regulación de la Expresión Génica , Memoria Inmunológica/genética , Interleucina-15/metabolismo , Interleucina-7/metabolismo , Ratones , Ratones Endogámicos C57BL , Factores de TranscripciónRESUMEN
OBJECTIVES: The differentiation of CD4+ T cells is regulated by a complex and fine signaling pathway composed of many molecules during immune response, and the molecular mechanism for regulating T-bet expression is unclear. Mediator complex subunit 1 (Med1) can combine with a variety of co-factors to regulate gene transcription, promote cell proliferation and survival, and affect invariant natural killer T cell (iNKT) development. This study aims to investigate the effect of Med1 on T cell development and CD4+ T cell differentiation in immune response. METHODS: Mice with T cell-specific knockout of Med1 gene (Med1F/FCD4cre+, KO) were constructed and verified. The percentage and number of CD4+ and CD8+ T cells in thymus, spleen, and lymph nodes of KO mice and control (Con) mice (Med1F/FCD4cre-) were detected by flow cytometry. After 8 days of infection with lymphocytic choriomeningitis virus (LCMV), the percentage and number of CD4+ T cells or antigen-specific (GP66+) CD4+ T cells, the percentage and number of Th1 cells (Ly6c+PSGL1+) in CD4+ T cells or antigen-specific CD4+ T cells were examined in the spleen of mice. Moreover, the fluorescence intensity of T-bet in CD4+ T cells or antigen-specific CD4+ T cells was analyzed. RESULTS: Compared with the Con group, the percentage and number of CD4+ T cells and CD8+ T cells in the thymus, CD4+ T cells in the spleen and lymph nodes of the KO group showed no significant differences (all P>0.05), but the percentage and number of CD8+ T cells in the spleen and lymph nodes of the KO group were diminished significantly (all P<0.05). After 8 days of infection with LCMV, there was no significant difference in the percentage and number of CD4+ T cells or antigen-specific CD4+ T cells in the spleen between the KO group and the Con group (all P>0.05), while in comparison with the Con group, the percentage and number of Th1 cells in CD4+ T cells or antigen-specific CD4+ T cells, and the expression of T-bet in CD4+ T cells or antigen-specific CD4+ T cells were significantly reduced in the spleen of the KO group (all P<0.05). CONCLUSIONS: Specific knockout of Med1 in T cells does not affect the development of CD4+ and CD8+ T cells in the thymus, but does affect the maintenance of peripheral CD8+ T cells. In the immune response, Med1 gene deletion affects the expression of transcription factor T-bet, which in turn to reduce Th1 cell differentiation.
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Linfocitos T CD8-positivos , Subunidad 1 del Complejo Mediador , Ratones , Animales , Linfocitos T CD8-positivos/metabolismo , Subunidad 1 del Complejo Mediador/metabolismo , Inmunidad , Diferenciación Celular , Virus de la Coriomeningitis Linfocítica/metabolismo , Células TH1/metabolismo , Linfocitos T CD4-Positivos/metabolismo , Ratones Endogámicos C57BLRESUMEN
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 TCRß 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 TCRß expression-mediated ß-selection and activating parallel cell survival pathways.
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Activación de Linfocitos , Timocitos , Animales , Diferenciación Celular , Linaje de la Célula , Supervivencia Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Timo/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Under steady-state conditions, the pool size of peripheral CD8+ T cells is maintained through turnover and survival. Beyond TCR and IL-7R signals, the underlying mechanisms are less well understood. In the present study, we found a significant reduction of CD8+ T cell proportion in spleens but not in thymi of mice with T cell-specific deletion of Mediator Subunit 1 (Med1). A competitive transfer of wild-type (WT) and Med1-deficient CD8+ T cells reproduced the phenotype in the same recipients and confirmed intrinsic role of Med1. Furthermore, we observed a comparable degree of migration and proliferation but a significant increase of cell death in Med1-deficient CD8+ T cells compared with WT counterparts. Finally, Med1-deficient CD8+ T cells exhibited a decreased expression of interleukin-7 receptor α (IL-7Rα), down-regulation of phosphorylated-STAT5 (pSTAT5) and Bim up-regulation. Collectively, our study reveals a novel role of Med1 in the maintenance of CD8+ T cells through IL-7Rα/STAT5 pathway-mediated cell survival.
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Linfocitos T CD8-positivos , Subunidad 1 del Complejo Mediador/inmunología , Receptores de Interleucina-7/inmunología , Bazo/inmunología , Animales , Apoptosis , Células de la Médula Ósea , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Supervivencia Celular , Células Cultivadas , Subunidad 1 del Complejo Mediador/genética , Ratones , Ratones Noqueados , Ratones Transgénicos , Transducción de Señal , Bazo/citologíaRESUMEN
γδ NKT cells are neonatal-derived γδ T lymphocytes that are grouped together with invariant NKT cells based on their shared innate-like developmental program characterized by the transcription factor PLZF (promyelocytic leukemia zinc finger). Previous studies have demonstrated that the population size of γδ NKT cells is tightly controlled by Id3-mediated inhibition of E-protein activity in mice. However, how E proteins promote γδ NKT cell development and expansion remains to be determined. In this study, we report that the transcription factor Egr2, which also activates PLZF expression in invariant NKT cells, is essential for regulating γδ NKT cell expansion. We observed a higher expression of Egr family genes in γδ NKT cells compared with the conventional γδ T cell population. Loss of function of Id3 caused an expansion of γδ NKT cells, which is accompanied by further upregulation of Egr family genes as well as PLZF. Deletion of Egr2 in Id3-deficient γδ NKT cells prevented cell expansion and blocked PLZF upregulation. We further show that this Egr2-mediated γδ NKT cell expansion is dependent on c-Myc. c-Myc knockdown attenuated the proliferation of Id3-deficient γδ NKT cells, whereas c-Myc overexpression enhanced the proliferation of Id3/Egr2-double-deficient γδ NKT cells. Therefore, our data reveal a regulatory circuit involving Egr2-Id3-E2A, which normally restricts the population size of γδ NKT cells by adjusting Egr2 dosage and c-Myc expression.
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Proliferación Celular/fisiología , Proteína 2 de la Respuesta de Crecimiento Precoz/inmunología , Regulación de la Expresión Génica/inmunología , Proteínas Inhibidoras de la Diferenciación/inmunología , Células T Asesinas Naturales/inmunología , Proteínas Proto-Oncogénicas c-myc/inmunología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Proteínas Inhibidoras de la Diferenciación/genética , Ratones , Ratones Noqueados , Células T Asesinas Naturales/citología , Proteína de la Leucemia Promielocítica con Dedos de Zinc/genética , Proteína de la Leucemia Promielocítica con Dedos de Zinc/inmunología , Proteínas Proto-Oncogénicas c-myc/genética , Receptores de Antígenos de Linfocitos T gamma-deltaRESUMEN
BACKGROUND The discovery of antineutrophil cytoplasm antibody (ANCA) makes the early diagnosis of primary vasculitis possible, and also has important guiding significance for the diagnosis and treatment of secondary vasculitis. This study aimed to investigate the clinical significance of ANCA. MATERIAL AND METHODS ANCA was detected by indirect immunofluorescence assay (IIF), and anti-myeloperoxidase (MPO) antibody, and anti-proteinase 3 (PR3) antibody were detected by ELISA. The results were analyzed retrospectively. RESULTS Among 118 730 patients, a total of 5853 (4.93%) were positive for ANCA. In the positive cases, 3.98% were male and 6.33% were female, with significant differences (χ²=123.38, P<0.01). For ANCA, the department with the highest positive rate (15.06%) was the Department of Rheumatology, followed by 7.78% in the Department of Dermatology, 6.79% in the Department of Nephrology, and 5.72% in the Department of Traditional Chinese Medicine (TCM). Anti-PR3 and cANCA were highly specific in primary vasculitis (P<0.01). Anti-MPO and pANCA had high specificity for other autoimmune diseases (P<0.01). CONCLUSIONS ANCA has important guiding significance for vasculitis-related diseases. Therefore, it is important in the diagnosis and treatment of this disease and has value in clinical practice.
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Anticuerpos Anticitoplasma de Neutrófilos/sangre , Vasculitis/sangre , Adulto , China , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Centros de Atención Terciaria/estadística & datos numéricos , Vasculitis/diagnóstico , Vasculitis/inmunologíaRESUMEN
INTRODUCTION: Both innate and adaptive immune system undergo evolution from low to high vertebrates. Due to the limitation of conventional approaches in identifying broader spectrum of immune cells and molecules from various vertebrates, it remains unclear how immune molecules evolve among vertebrates. OBJECTIVES: Here, we utilized carry out comparative transcriptome analysis in various immune cells across seven vertebrate species. METHODS: Single-cell RNA sequencing (scRNA-seq). RESULTS: We uncovered both conserved and species-specific profiling of gene expression in innate and adaptive immunity. Macrophages exhibited highly-diversified genes and developed sophisticated molecular signaling networks along with evolution, indicating effective and versatile functions in higher species. In contrast, B cells conservatively evolved with less differentially-expressed genes in analyzed species. Interestingly, T cells represented a dominant immune cell populations in all species and unique T cell populations were identified in zebrafish and pig. We also revealed compensatory TCR cascade components utilized by different species. Inter-species comparison of core gene programs demonstrated mouse species has the highest similarity in immune transcriptomes to human. CONCLUSIONS: Therefore, our comparative study reveals gene transcription characteristics across multiple vertebrate species during the evolution of immune system, providing insights for species-specific immunity as well as the translation of animal studies to human physiology and disease.
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Inmunidad Adaptativa , Inmunidad Innata , Transcriptoma , Animales , Humanos , Ratones , Inmunidad Adaptativa/genética , Macrófagos , Porcinos , Pez Cebra/genética , Inmunidad Innata/genéticaRESUMEN
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.
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Proteína ADAM17 , Linfocitos T CD8-positivos , Diferenciación Celular , Proteína ADAM17/genética , Proteína ADAM17/inmunología , Linfocitos T CD8-positivos/inmunología , Animales , Ratones , Humanos , Diferenciación Celular/inmunología , Diferenciación Celular/genética , Diferenciación Celular/efectos de los fármacos , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/patologíaRESUMEN
T cells are crucial for immune functions to maintain health and prevent disease. T cell development occurs in a stepwise process in the thymus and mainly generates CD4+ and CD8+ T cell subsets. Upon antigen stimulation, naïve T cells differentiate into CD4+ helper and CD8+ cytotoxic effector and memory cells, mediating direct killing, diverse immune regulatory function, and long-term protection. In response to acute and chronic infections and tumors, T cells adopt distinct differentiation trajectories and develop into a range of heterogeneous populations with various phenotype, differentiation potential, and functionality under precise and elaborate regulations of transcriptional and epigenetic programs. Abnormal T-cell immunity can initiate and promote the pathogenesis of autoimmune diseases. In this review, we summarize the current understanding of T cell development, CD4+ and CD8+ T cell classification, and differentiation in physiological settings. We further elaborate the heterogeneity, differentiation, functionality, and regulation network of CD4+ and CD8+ T cells in infectious disease, chronic infection and tumor, and autoimmune disease, highlighting the exhausted CD8+ T cell differentiation trajectory, CD4+ T cell helper function, T cell contributions to immunotherapy and autoimmune pathogenesis. We also discuss the development and function of γδ T cells in tissue surveillance, infection, and tumor immunity. Finally, we summarized current T-cell-based immunotherapies in both cancer and autoimmune diseases, with an emphasis on their clinical applications. A better understanding of T cell immunity provides insight into developing novel prophylactic and therapeutic strategies in human diseases.
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Enfermedades Autoinmunes , Linfocitos T CD8-positivos , Humanos , Linfocitos T CD4-Positivos , Subgrupos de Linfocitos T , Enfermedades Autoinmunes/genética , TimoRESUMEN
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 RNA-Seq 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.
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Tolerancia Inmunológica , Linfocitos T Reguladores , Animales , Humanos , Ratones , Autoinmunidad , Ácidos Grasos/genética , Ácidos Grasos/metabolismo , Subunidad alfa de la Proteína Trifuncional Mitocondrial/metabolismoRESUMEN
Innate and adaptive immunity synergistically contribute to an effective anti-tumor response. Therapeutics targeting T cells, such as immune checkpoint inhibitors and engineered chimeric antigen receptor (CAR) T cells have shown promising effects in patients with hematologic malignancies. These strategies aim to strengthen T cell activation, proliferation, survival, and/or effector function by altering T cell receptor (TCR) signaling, co-stimulation, and cytokine gene expression. Toll-like receptors (TLRs) are primarily expressed by innate immune cells and are known to recognize pathogen-associated molecular patterns (PAMPs). However, increasing studies have highlighted their intrinsic contribution to T cell-mediated anti-tumor responses. Here, we have summarized the advances in our understanding of the ability of different types of TLRs and their downstream signaling pathways to activate anti-tumor immunity in T cells. Additionally, we discuss the potential for TLR agonists in improving the therapeutic effects when used in combination with other treatments.
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Neoplasias , Linfocitos T , Inmunidad Adaptativa , Humanos , Inmunidad Innata/fisiología , Activación de Linfocitos , Neoplasias/terapia , Transducción de Señal , Receptores Toll-LikeRESUMEN
[This corrects the article DOI: 10.1021/acsomega.2c02222.].
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Understanding the pore heterogeneity of tectonic coal and primary-structure coal is of great significance for predicting and preventing tectonic coal. This study adopts the low-temperature nitrogen adsorption method, mercury injection experiment, and other methods, combined with fractal theory, to quantitatively analyze the pore distribution of coal samples inside and outside the outburst cavities of the Sanjia coal mine. The experiments have shown that the contents of aliphatic functional groups and hydrogen in tectonic coal are higher than those of aromatic structural functional groups. Raw coal has more straight chains than side chains, whereas aliphatic hydrocarbon mostly has short chains, and the branching degree is high. Soft and primary-structure coals have similar elemental content and tectonic effects endow the coal with better connectivity. The pores are filled with particles and flakes, and the surfaces of tectonic coal have more pores and fissures on them. According to the experimental curve, the pores are divided into five types. The pore size of primary-structure coal is mainly type II pores, and the pore size distribution of tectonic coal is relatively wide, with the majority being class I and class II pores. The specific surface area of tectonic coal is 60.7% more than that of primary-structure coal. The box fractal dimension of coal decreases with the increase in scanning electron microscopy (SEM) magnification. The minimum fractal dimension of tectonic coal is 2.49, which is 7.8% lower than the peak of 2.70. It can be seen from the fractal dimension that the fractal dimensions of pore types II, III, and IV are rougher.
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Upon virus infection, CD8+ T cell accumulation is tightly controlled by simultaneous proliferation and apoptosis. However, it remains unclear how TCR signal coordinates these events to achieve expansion and effector cell differentiation. We found that T cell-specific deletion of nuclear helicase Dhx9 led to impaired CD8+ T cell survival, effector differentiation, and viral clearance. Mechanistically, Dhx9 acts as the key regulator to ensure LCK- and CD3ε-mediated ZAP70 phosphorylation and ERK activation to protect CD8+ T cells from apoptosis before proliferative burst. Dhx9 directly regulates Id2 transcription to control effector CD8+ T cell differentiation. The DSRM and OB_Fold domains are required for LCK binding and Id2 transcription, respectively. Dhx9 expression is predominantly increased in effector CD8+ T cells of COVID-19 patients. Therefore, we revealed a previously unknown regulatory mechanism that Dhx9 protects activated CD8+ T cells from apoptosis and ensures effector differentiation to promote antiviral immunity independent of nuclear sensor function.
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Antivirales/farmacología , Infecciones por Arenaviridae/prevención & control , Linfocitos T CD8-positivos/inmunología , COVID-19/prevención & control , ARN Helicasas DEAD-box/metabolismo , Inmunidad Innata , Proteínas de Neoplasias/metabolismo , Animales , Infecciones por Arenaviridae/inmunología , Infecciones por Arenaviridae/metabolismo , Infecciones por Arenaviridae/patología , COVID-19/inmunología , COVID-19/metabolismo , COVID-19/patología , Diferenciación Celular , ARN Helicasas DEAD-box/genética , Humanos , Activación de Linfocitos , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones , Proteínas de Neoplasias/genética , SARS-CoV-2/fisiología , Replicación ViralRESUMEN
T-cell development in the thymus undergoes the process of differentiation, selective proliferation, and survival from CD4-CD8- double negative (DN) stage to CD4+CD8+ double positive (DP) stage prior to the formation of CD4+ helper and CD8+ cytolytic T cells ready for circulation. Each developmental stage is tightly regulated by sequentially operating molecular networks, of which only limited numbers of transcription regulators have been deciphered. Here, we identified Zfp335 transcription factor as a new player in the regulatory network controlling thymocyte development in mice. We demonstrate that Zfp335 intrinsically controls DN to DP transition, as T-cell-specific deficiency in Zfp335 leads to a substantial accumulation of DN3 along with reduction of DP, CD4+, and CD8+ thymocytes. This developmental blockade at DN stage results from the impaired intracellular TCRß (iTCRß) expression as well as increased susceptibility to apoptosis in thymocytes. Transcriptomic and ChIP-seq analyses revealed a direct regulation of transcription factors Bcl6 and Rorc by Zfp335. Importantly, enhanced expression of TCRß and Bcl6/Rorc restores the developmental defect during DN3 to DN4 transition and improves thymocytes survival, respectively. These findings identify a critical role of Zfp335 in controlling T-cell development by maintaining iTCRß expression-mediated ß-selection and independently activating cell survival signaling.
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Supervivencia Celular , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Linfocitos T/metabolismo , Factores de Transcripción/metabolismo , Animales , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Diferenciación Celular , Ratones , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Timocitos/metabolismo , Timo/metabolismo , Dedos de ZincRESUMEN
The gas emission rate of boreholes is one of the most important indices for coal and gas outburst prediction. In this work, instantaneous gas emission velocity and environmental effects on borehole gas emission were studied. Through theoretical analysis, the mechanism of crack propagation in the coal borehole was clarified, and the effect of soft and hard coal on gas desorption and gas emission. The results of numerical simulations also indicated that the initial gas emission has a function relationship to the drilling distance and the physical characteristics of the coal seam. A novel dynamic testing technology was proposed to obtain gas emission velocity. Laboratory experiments under adsorption and desorption of CO2 and N2 were performed using coal samples from Xuehu, Fenghui, Weishe, and Wuzhong coal mines. The data of initial gas emission under different coal samples were recorded, and the fitting curves were obtained. The results show a positive correlation between initial gas emission and drilling depth. However, abnormal would occur when the drill pipe enters the soft stratification, and the maximum value of the initial gas emission of the abnormal part is 3.8 times the normal value, which indicates a high degree of sensibility to soft stratification. The results were revealed the dynamic gas emission law of boreholes.