RESUMEN
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.
Asunto(s)
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.
RESUMEN
The spleen is a vital organ for the immune system, while splenectomy may be necessary for various reasons. However, there is limited research on the impact of splenectomy on T cell function in peripheral lymph nodes as a compensatory mechanism in preventing infections. This study aimed to investigate the characteristics and function of CD8+ and CD4+ T cells in different peripheral lymph nodes during viral infection using a well-established splenectomy model. The results revealed that splenectomy caused an increase in CD8+GP33+ T cells in the mesenteric lymph nodes (MLN). Moreover, we demonstrated that splenectomy resulted in an increase of effector KLRG1+ T cells in the MLN. Additionally, the number of CD4+ cytotoxic T cells (CD4 CTLs) was also elevated in the peripheral lymph nodes of mice with splenectomy. Surprisingly, aged mice exhibited a stronger compensatory ability than adult mice, as evidenced by an increase in effector CD8+ T cells in all peripheral lymph nodes. These findings provide compelling evidence that T cells in MLN play a crucial role in protecting individuals with splenectomy against viral infections. The study offers new insights into understanding the changes in the immune system of individuals with splenectomy and highlights the potential compensatory mechanisms involved by T cells in peripheral lymph nodes.
Asunto(s)
Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Ganglios Linfáticos , Esplenectomía , Animales , Ganglios Linfáticos/inmunología , Ratones , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD4-Positivos/inmunología , Ratones Endogámicos C57BL , Bazo/inmunologíaRESUMEN
Ferroptosis is a new form of regulated cell death featuring iron-dependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosis-based cancer therapy in eradicating refractory malignancies that are resistant to apoptosis-based conventional therapies. In recent years, studies have reported a number of ferroptosis inducers that can increase the vulnerability of tumor cells to ferroptosis by regulating ferroptosis-related signaling pathways. Encouraged by the rapid development of ferroptosis-driven cancer therapies, interdisciplinary fields that combine ferroptosis, pharmaceutical chemistry, and nanotechnology are focused. First, the prerequisites and metabolic pathways for ferroptosis are briefly introduced. Then, in detail emerging ferroptosis inducers designed to boost ferroptosis-induced tumor therapy, including metal complexes, metal-based nanoparticles, and metal-free nanoparticles are summarized. Subsequently, the application of synergistic strategies that combine ferroptosis with apoptosis and other regulated cell death for cancer therapy, with emphasis on the use of both cuproptosis and ferroptosis to induce redox dysregulation in tumor and intracellular bimetallic copper/iron metabolism disorders during tumor treatment is discussed. Finally, challenges associated with clinical translation and potential future directions for potentiating cancer ferroptosis therapies are highlighted.
Asunto(s)
Ferroptosis , Nanomedicina , Neoplasias , Ferroptosis/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Nanomedicina/métodos , Animales , Complejos de Coordinación/química , Complejos de Coordinación/farmacología , Complejos de Coordinación/uso terapéuticoRESUMEN
The present study aimed to explore the effects of different exercise modes on neuromuscular junction (NMJ) and metabolism of skeletal muscle-related proteins in aging rats. Ten from 38 male Sprague-Dawley (SD) rats (3-month-old) were randomly selected into young (Y) group, while the rest were raised to 21 months old and randomly divided into elderly control (O), endurance exercise (EN) and resistance exercise (R) groups. After 8 weeks of corresponding exercises training, the gastrocnemius muscles of rats were collected, and the expression of S100B in Schwann cells was detected by immunofluorescence staining. Western blot was used to detect the protein expression levels of agglutinate protein (Agrin), low-density lipoprotein receptor-related protein 4 (Lrp4), muscle- specific kinase protein (MuSK), downstream tyrosine kinase 7 (Dok7), phosphorylated protein kinase B (p-Akt), phosphorylated mammalian target rapamycin (p-mTOR), and phosphorylated forkhead box O1 (p-FoxO1) in rat gastrocnemius muscles. The results showed that, endurance and resistance exercises increased the wet weight ratio of gastrocnemius muscle in the aging rats. The protein expression of S100B in the R group was significantly higher than those in the O and EN groups. Proteins related to NMJ function, including Agrin, Lrp4, MuSK, and Dok7 were significantly decreased in the O group compared with those in the Y group. Resistance exercise up-regulated these four proteins in the aging rats, whereas endurance exercise could not reverse the protein expression levels of Lrp4, MuSK and Dok7. Regarding skeletal muscle-related proteins, the O group showed down-regulated p-Akt, and p-mTOR protein expression levels and up-regulated p-FoxO1 protein expression level, compared to the Y group. Resistance and endurance exercises reversed the changes in p-mTOR and p-FoxO1 protein expression in the aging rats. These findings demonstrate that both exercise modes can enhance NMJ function, increase protein synthesis and reduce the catabolism of skeletal muscle-related proteins in aging rats, with resistance exercise showing a more pronounced effect.
Asunto(s)
Envejecimiento , Músculo Esquelético , Unión Neuromuscular , Condicionamiento Físico Animal , Ratas Sprague-Dawley , Animales , Masculino , Envejecimiento/metabolismo , Envejecimiento/fisiología , Ratas , Músculo Esquelético/metabolismo , Condicionamiento Físico Animal/fisiología , Unión Neuromuscular/metabolismo , Unión Neuromuscular/fisiología , Proteínas Musculares/metabolismo , Entrenamiento de Fuerza/métodos , Proteína Forkhead Box O1RESUMEN
The distortion of the cellular membrane transport pathway has a profound impact on cell dynamics and can drive serious physiological consequences during the process of cell sorting. SNX17 is a member of the Sorting Nexin (SNX) family and plays a crucial role in protein sorting and transport in the endocytic pathway. SNX17, SNX27, and SNX31 belong to the SNX-FERM subfamily and possess the FERM domain, which can assist in endocytic transport and lysosomal degradation. The binding partners of SNX27 have been discovered to number over 100, and SNX27 has been linked to the development of Alzheimer's disease progression, tumorigenesis, cancer progression, and metastasis. However, the role and potential mechanisms of SNX17 in human health and disease remain poorly understood, and the function of SNX17 has not been fully elucidated. In this review, we summarize the structure and basic functions of SNX protein, focusing on providing current evidence of the role and possible mechanism of SNX17 in human neurodegenerative diseases and cardiovascular diseases.
RESUMEN
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.
Asunto(s)
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
Purpose: The aim of this study was to investigate the effect of blood flow restriction (BFR) combined with low-intensity resistance training (RT) on cardiovascular risk factors in obese individuals. Methods: Twenty-six male obese college students were recruited and randomly assigned to a control group (CON, n = 8), a low-intensity RT group (RT, n = 9), and a combined BFR training and low-intensity RT group (BFRT, n = 9). Results: The subjects in BFRT group showed significant reductions in body fat percentage and waist-to-hip ratio and a significant increase in lean mass and muscle mass; the peak torque, peak power, and endurance ratio of knee extensors and elbow flexors were significantly upregulated; the root mean square (RMS) for the medial femoral muscle, lateral femoral muscle and biceps significantly increased; the diastolic blood pressure (DBP) showed a significant decrease. The BFRT group also showed significant up-regulations in RMS of the difference between the adjacent R-R intervals (RMSSD), high-frequency power (HF) of parasympathetic modulatory capacity, the standard deviation of R-R intervals (SDNN) of overall heart rate variability (HRV) changes and low-frequency power (LF) of predominantly sympathetic activity. In addition, glycated hemoglobin (HbA1C), insulin resistance index (HOMA-IR) and fasting blood glucose (FBG) were all significantly downregulated in BFRT group. In parallel, low-density lipoprotein (LDL-C) significantly reduced while high-density lipoprotein (HDL-C) significantly increased in BFRT group. Conclusion: BFR combined with low-intensity RT training effectively improved body composition index, increased muscle mass, improved neuromuscular activation, enhanced muscle strength and endurance, which in turn improved abnormal glucolipid metabolism and enhanced cardiac autonomic regulation.