Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells pl...Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells play a role in many events that require urgent intervention,especially anaphylaxis,has led to a more detailed study of these cells.The diseases also caused by dysfunctions of mast cells have been examined in many circumstances.For instance,mast cell activation syndrome is known as an augmented number of cells due to decreased cell death,resulting in clinical symptoms affecting many systems.The main common symptoms include flushing,hypotension,urticaria,angioedema,headache,vomiting and diarrhea.Although the underlying mechanism is not yet clearly known,we aim to review the literature in a broad perspective and bring together the existing knowledge in the light of the literature due to the diversity of its involvement in the body and the fact that it is a little known syndrome.展开更多
Perforin is a pore-forming protein engaged mainly in mediating target T cell death and is employed by cytotoxic T lymphocytes (CTLs) and natural killer cells. However, whether it also plays a role in conventional C...Perforin is a pore-forming protein engaged mainly in mediating target T cell death and is employed by cytotoxic T lymphocytes (CTLs) and natural killer cells. However, whether it also plays a role in conventional CD4^+ T cell function remains unclear. Here we report that in perforin-deficient (PKO) mice, CD4^+ T cells are hyperproliferative in response to T cell receptor (TCR) stimulation. This feature of hyperproliferation is accompanied by the enhancement both in cell division and in IL-2 secretion. It seems that the perforin deficiency does not influence T cell development in thymus spleen and lymph node. In vivo, perforin deficiency results in increased antigen-specific T cell proliferation and antibody production. Furthermore, PKO mice are more susceptible to experimental autoimmune uveitis. To address the molecular mechanism, we found that after TCR stimulation, CD4^+ T cells from PKO mice display an increased intracellular calcium flux and subsequently enhance activation of transcription factor NFAT1. Our results indicate that perforin plays a negative role in regulating CD4^+ T cell activation and immune response by affecting TCR-dependent Ca^2+ signaling.展开更多
Mesenchymal stromal cells(MSCs) possess great therapeutic advantages due to their ability to produce a diverse array of trophic/growth factors related to cytoprotection and immunoregulation.MSC activation via specific...Mesenchymal stromal cells(MSCs) possess great therapeutic advantages due to their ability to produce a diverse array of trophic/growth factors related to cytoprotection and immunoregulation.MSC activation via specific receptors is a crucial event for these cells to exert their immunosuppressive response.The aryl-hydrocarbon receptor(Ah R) is a sensitive molecule for external signals and it is expressed in MSCs and,upon positive activation,may potentially regulate the MSC-associated immunomodulatory function.Consequently,signalling pathways linked to Ah R activation can elucidate some of the molecular cascades involved in MSC-mediated immunosuppression.In this minireview,we have noted some important findings concerning MSC regulation via Ah R,highlighting that its activation is associated with improvement in migration and immunoregulation,as well as an increase in pro-regenerative potential.Thus,Ah R-mediated MSC activation can contribute to new perspectives on MSC-based therapies,particularly those directed at immune-associated disorders.展开更多
This paper described T cell proliferative response by an alternative pathway in normal subjects and In patients with malignant diseases. Two McAbs, Anti-CCTl and Lo-CD2-act recognizing two distinct epitopes on E-recep...This paper described T cell proliferative response by an alternative pathway in normal subjects and In patients with malignant diseases. Two McAbs, Anti-CCTl and Lo-CD2-act recognizing two distinct epitopes on E-receptor (CD2) were used to costimulate PBMC. Proliferative responsiveness was measured by 3H-thymidine incorporation. It was found that 82% of 72 nonnal subjects gave proliferative response whereas only 23% of the 93 patients did. The average cpm±SD in patients with bladder cancer (118±2314), kidney cancer (1619±2719) or lymphoma (2518±4057) was significantly lower than that in normal subjects (4935±2314), (P<0.001). These results indicate that T cell proliferation through the alternative pathway was significantly depressed in patients with cancer, and this can be used as a new parameter to monitor the immune status of cancer patients.展开更多
Mast cell activation syndrome(MCAS)includes a group of disorders that result in the inappropriate release of inflammatory mediators from mast cells.These mediators can affect multiple organ systems and lead to signifi...Mast cell activation syndrome(MCAS)includes a group of disorders that result in the inappropriate release of inflammatory mediators from mast cells.These mediators can affect multiple organ systems and lead to significant morbidity,and possible fatality.Although reactions,typically in response to various nonspecific stimuli,are usually mild,they may put those with MCAS at increased risk of anaphylaxis.In this case report,we present two clinical scenarios of MCAS,and identify possible factors triggering mast cell mediator release.We also define a preoperative preventive pathway,outline anesthetic considerations,and discuss the management of immediate hypersensitivity reactions in patients with MCAS.Meticulous preoperative preparation,avoidance of triggers,and development of a plan to treat possible adverse organ responses are paramount of good outcomes.展开更多
To investigate whether estradiol (E2) plays a role in cell-contact-dependent regulatory mechanism of T cell activation, we studied the role of E2 in regulating gene transcription of CTLA-4, ICOS, B7-1, B7-2 and B7h ...To investigate whether estradiol (E2) plays a role in cell-contact-dependent regulatory mechanism of T cell activation, we studied the role of E2 in regulating gene transcription of CTLA-4, ICOS, B7-1, B7-2 and B7h in vitro. The splenic cells of normal female BALB/c mice were activated by ConA. Then the cells were cultured with E2 (100 pg/ml or 50 ng/ml) for 24 h or 48 h, respectively. The cell proliferation was measured by MTF assay and the expression of the co-stimulatory molecules mRNA was examined by RT-PCR analysis. We found that E2 (100 pg/ml, physiological level) stimulated the acti- vated spleen cells proliferation; inhibited CTLA-4, ICOS, TGF-β and IL-10 gene transcription; promoted B7-1 and B7-2 gene transcription. E2 (50 ng/ml, pregnant level) inhibited the proliferation of the activated splenic cells; promoted CTLA-4, B7-1, IL-10 but inhibited B7-2 and TGF-β gene transcription. Therefore, we conclude that the effects of E2 on T cell activation are partially through its regulation on the co-stimulatory molecules. The co-stimulatory molecules are crucial components of the cell-contact dependent regulatory mechanism, and E2 may regulate T cell activation by this mechanism.展开更多
The spatial arrangement of activating ligands is known to have great influence on T cell activation.However,independently studying each ligand’s spatial organization parameter that affects T cell activation remains a...The spatial arrangement of activating ligands is known to have great influence on T cell activation.However,independently studying each ligand’s spatial organization parameter that affects T cell activation remains a great challenge.Here,with DNA origami,we precisely organized the CD3ɛantibodies simulating T cell receptor(TCR)ligands and CD28 antibodies simulating co-stimulatory ligands to interrogate the independent role of TCR-ligand spacing and local copy numbers as well as the spacing between TCR ligands and co-stimulatory ligands on T cell activation.We found that T cell activation benefited fromlocally concentrated TCR ligands with a shorter spacing and was maximized by an∼38 nm spacing between TCR ligands and co-stimulatory ligands.The T cell expander constructed based on our findings could efficiently expand CD8+T cells for tumor immunotherapy.Thus,the DNA nanostructurebased ligands’precise arrangement can be a unique tool in studying immune cell activations and cellbased immunotherapies.展开更多
Abstract The lipids present in hepatic stellate cells (HSCs) lipid droplets include retinyl ester, triglyceride, cholesteryl ester, cholesterol, phospholipids and free fatty acids. Activation of HSCs is crucial to t...Abstract The lipids present in hepatic stellate cells (HSCs) lipid droplets include retinyl ester, triglyceride, cholesteryl ester, cholesterol, phospholipids and free fatty acids. Activation of HSCs is crucial to the development of fibrosis in liver disease. During activation, HSCs transform into myofibroblasts with concomitant loss of their lipid droplets and production of excessive extracellular matrix. Release of lipid droplets containing retinyl esters and triglyceride is a defining feature of activated HSCs. Accumulating evidence supports the proposal that recovering the accumulation of lipids would inhibit the activation of HSCs. In healthy liver, quiescent HSCs store 80% of total liver retinols and release them depending on the extracellular retinol status. However, in injured liver activated HSCs lose their retinols and produce a considerable amount of extracelhilar matrix, subsequently leading to liver fibrosis. Further findings prove that lipid metabolism of HSCs is closely associated with its activation, yet relationship between activated HSCs and the lipid metabolism has remained mysterious.展开更多
Dendritic cells(DC)are the major antigen-presenting cells bridging innate and adaptive immunity,a function they perform by converting quiescent DC to active,mature DC with the capacity to activate naı¨ve T cells....Dendritic cells(DC)are the major antigen-presenting cells bridging innate and adaptive immunity,a function they perform by converting quiescent DC to active,mature DC with the capacity to activate naı¨ve T cells.They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues.Here,wedemonstrate thatmyeloid cell-specific genetic deletion of PTP1B(LysM PTP1B)leads to defects in lipopolysaccharide-driven bone marrow-derivedDC(BMDC)activation associated with increased levels of phosphorylated Stat3.We showthatmyeloid cell-specific PTP1Bdeletion also causes decreased migratory capacity of epidermal DC,aswell as reduced CCR7 expression and chemotaxis to CCL19 by BMDC.PTP1B deficiency in BMDC also impairs their migration in vivo.Further,immature LysM PTP1B BMDC display fewer podosomes,increased levels of phosphorylated Src at tyrosine 527,and loss of Src localization to podosome puncta.In co-culture with T cells,LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC.Finally,LysMPTP1BBMDCfail to present antigen to T cells as efficiently as controlBMDC.These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation.展开更多
Adapter proteins can regulate the gene transcriptions in disparate signaling pathway by interacting with multiple signaling molecules, including T cell activation signaling. Nuclear receptor binding protein (NRBP), ...Adapter proteins can regulate the gene transcriptions in disparate signaling pathway by interacting with multiple signaling molecules, including T cell activation signaling. Nuclear receptor binding protein (NRBP), a novel adapter protein, represents a small family of evolutionarily conserved proteins with homologs in Caenorhabditis elegans (C. elegans), Drosophila melanogaster (i). melanogaster), mouse and human. Here, we demonstrated that overexpression of NRBP in Jurkat TAg cells specifically impairs T cell receptor (TCR) or phorbol myristate acetate (PMA) /ionomycin-mediated signaling leading to nuclear factor of activated T cells (NFAT) promoter activation. Furthermore, the N-terminal of NRBP is necessary for its regulation of NFAT activation. Finally, we showed that NRBP has minimal effect on both TCR- and PMA-induced CD69 up-regulation in Jurkat TAg cells, which suggests that NRBP may function downstream of protein kinase C (PKC) /Ras pathway.展开更多
Objective To investigate the relationship between expression of somatostatin receptors(SSTRs) and activation of rat hepatic stellate cell (HSC). Methods HSCs were isolated from rats by in situ perfusion and single-ste...Objective To investigate the relationship between expression of somatostatin receptors(SSTRs) and activation of rat hepatic stellate cell (HSC). Methods HSCs were isolated from rats by in situ perfusion and single-step density gradient centrifugation, and then SSTR1-5 mRNA levels in the differentiated first passage HSCs were detected by means of reverse transcription polymerase chain reaction. On the other hand, hepatic fibrosis was induced in adult male Sprague-Dawley rats by carbon tetrachloride intoxication, and the expression of SSTR1-5 in normal as well as fibrotic liver was measured by immunohistochemical staining. Results SSTR mR-NA and SSTR could not be found in freshly isolated rat HSCs and normal rat liver. But SSTR1-3 mRNA appeared as HSCs became wholly activated, and SSTR1-3 could also be identified on the membrane of activated HSCs in the peri-sinusoid space, fibrous septa, etc. Conclusion The expression of SSTR1-3 in the rat HSC is closely related to its activation. This may reflect one of the main negative regulation mechanisms in the course of HSC activation.展开更多
One of the hallmarks of live cells is the asymmetric distribution of lipids across their plasma membrane.Changes in this asymmetry due to lipid"scrambling"result in phosphatidylserine exposure at the cell su...One of the hallmarks of live cells is the asymmetric distribution of lipids across their plasma membrane.Changes in this asymmetry due to lipid"scrambling"result in phosphatidylserine exposure at the cell surface that is detected by annexin V staining.This alteration is observed during cell death processes such as apoptosis,and during physiological responses such as platelet degranulation and membrane repair.Previous studies have shown that activation of NK cells is accompanied by exposure of phosphatidylserine at the cell surface.While this response was thought to be indicative of ongoing NK cell death,it may also reflect the regulation of NK cell activation in the absence of cell death.Herein,we found that NK cell activation was accompanied by rapid phosphatidylserine exposure to an extent proportional to the degree of NK cell activation.Through enforced expression of a lipid scramblase,we provided evidence that activation-induced lipid scrambling in NK cells is reversible and does not lead to cell death.In contrast,lipid scrambling attenuates NKcell activation.This response was accompanied by reduced cell surface expression of activating receptors such as 2B4,and by loss of binding of Src family protein tyrosine kinases Fyn and Lck to the inner leaflet of the plasma membrane.Hence,lipid scrambling during NK cell activation is,at least in part,a physiological response that reduces the NK cell activation level.This effect is due to the ability of lipid scrambling to alter the distribution of membrane-associated receptors and kinases required for NK cell activation.展开更多
Objective To investigate the expression of B cell activation factor of the TNF family (BAFF) gene between human normal and inflamed fallopian tubes. Methods Tissue samples of human normal fallopian tube (n=20) and...Objective To investigate the expression of B cell activation factor of the TNF family (BAFF) gene between human normal and inflamed fallopian tubes. Methods Tissue samples of human normal fallopian tube (n=20) and inflamed fallopian tube (n=20) were collected. The expression of BAFF gene was determined by the real- time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Results BAFF immunostaining appeared on the cellular membrane and in the cytoplasm of tubal epithelial cells. Both BAFF protein and mRNA in normal fallopian tubes had lower levels than those in inflamed fallopian tubes (P〈0.01). Conclusion BAFF protein and mRNA are present in human tubal tissues. BAFF gene in human inflamed fallopian tube would have a high expression.展开更多
Gelatinase A (MMP-2) is considered to play a critical role in cell migration and invasion. The proteinase is secreted from the cell as an inactive zymogen. In vivo it is postulated that activation of progelationase A ...Gelatinase A (MMP-2) is considered to play a critical role in cell migration and invasion. The proteinase is secreted from the cell as an inactive zymogen. In vivo it is postulated that activation of progelationase A (proMMP-2) takes place on the cell surface mediated by membrane-type matrix metalloproteinases (MT-MMPs). Recent studies have demonstrated that proMMP-2 is recruited to the cell surface by interacting with tissue inhibitor of metalloproteinases-2 (TIMP-2) bound to MT1MMP by forming a ternary complex. bee MT1-MMP closely located to the ternary complex then activates proMMP-2 on the cell surface. MT1-MMP is found in cultured invasive cancer cells at the invadopodia. The MTMMP/TIMP-2/ MMP- 2 system t bus provides localized expression of proteolysis of the extracellular matrix required for cell migration.展开更多
AIM:To investigate the role of nuclear factor of activated T cell 2(NFAT2),the major NFAT protein in peripheral T cells,in sustained T cell activation and intractable inflammation in human ulcerative colitis(UC). METH...AIM:To investigate the role of nuclear factor of activated T cell 2(NFAT2),the major NFAT protein in peripheral T cells,in sustained T cell activation and intractable inflammation in human ulcerative colitis(UC). METHODS:We used two-dimensional gel-electrophoresis, immunohistochemistry,double immunohistochemical staining,and confocal microscopy to inspect the expression of NFAT2 in 107,15,48 and 5 cases of UC, Crohn's disease(CD),non-specific colitis,and 5 healthy individuals,respectively. RESULTS:Up-regulation with profound nucleo- translocation/activation of NFAT2 of lamina propria mononuclear cells(LPMC)of colonic mucosa was found specifically in the affected colonic mucosa from patients with UC,as compared to CD or NC(P<0.001,Kruskal- Wallis test).Nucleo-translocation/activation of NFAT2 primarily occurred in CD8+T,but was less prominent in CD4+T cells or CD20+B cells.It was strongly associated with the disease activity,including endoscopic stage (τ=0.2145,P=0.0281)and histologic grade(τ=0.4167, P<0.001). CONCLUSION:We disclose for the first time the nucleo-translocation/activatin of NFAT2 in lamina propria mononuclear cells in ulcerative colitis.Activation of NFAT2 was specific for ulcerative colitis and highly associated with disease activity.Since activation of NFAT2is implicated in an auto-regulatory positive feedback loop of sustained T-cell activation and NFAT proteins play key roles in the calcium/calcineurin signaling pathways,our results not only provide new insights into the mechanism for sustained intractable inflammation,but also suggest the calcium-calcineurin/NFAT pathway as a new therapeutic target for ulcerative colitis.展开更多
Objective To explore the correlation between endothelia cells activation and cytokines (ET-1, NO) levels in patients with pulmonary hypertension (PH), and to discuss their roles in the development of PH. Methods Twent...Objective To explore the correlation between endothelia cells activation and cytokines (ET-1, NO) levels in patients with pulmonary hypertension (PH), and to discuss their roles in the development of PH. Methods Twenty patients with simple ventricular septal defect (VSD) were chosen as controls, and 30 patients with PH were studied. Plasma levels of ET-1 and NO were measured by radioimmunoassay or colorimetric method. Before cardiopulmonary bypass was established, the specimens from right lung were fixed with formaldehyde solution, embedded with paraffin and stained by SP immunohistochemistry. Intercellular adhesion molecule-1 (ICAM-1) expression was measured through the determination of the light density with computer imaging technology. Results Compared with that of the patients with simple VSD, the light density of ICAM-1 and plasma level of ET-1 increased in patients with PH; but plasma level of NO decreased (P<0.05). Positive correlation was observed between ICAM-1 and ET-1/NO (P<0.05). Conclusion Endothelia cells activation and imbalance of ET-1/NO might play an important role in the development of PH.展开更多
A key feature that distinguishes cancer cells from all other cells is their capability to spread throughout the body.Although how cancer cells collectively migrate by following molecular rules which influence the stat...A key feature that distinguishes cancer cells from all other cells is their capability to spread throughout the body.Although how cancer cells collectively migrate by following molecular rules which influence the state of cell-cell adhesion contacts has been comprehensively formulated,the impact of physical interactions on cell spreading remains less understood.Cumulative effects of physical interactions exist as the interplay between various physical parameters such as(1)tissue surface tension,(2)viscoelasticity caused by collective cell migration,and(3)solid stress accumulated in the cell aggregate core region.This review aims to point out the role of these physical parameters in cancer cell spreading by considering and comparing the rearrangement of various mono-cultured cancer and epithelial model systems such as the fusion of two cell aggregates.While epithelial cells undergo volumetric cell rearrangement driven by the tissue surface tension,which directs cell movement from the surface to the core region of two-aggregate systems,cancer cells rather perform surface cell rearrangement.Cancer cells migrate toward the surface of the two-aggregate system driven by the solid stress while the surface tension is significantly reduced.The solid stress,accumulated in the core region of the two-aggregate system,is capable of suppressing the movement of epithelial cells that can undergo the jamming state transition;however,this stress enhances the movement of cancer cells.We have focused here on the multi-scale rheological modeling approaches that aimed at reproducing and understanding these biological systems.展开更多
α-Galactosylceramides, which can be recognized by natural killer T (NKT) cells, are now attracting more and more attention due to their therapeutic potential in cancer, infection and autoimmune diseases. Advances h...α-Galactosylceramides, which can be recognized by natural killer T (NKT) cells, are now attracting more and more attention due to their therapeutic potential in cancer, infection and autoimmune diseases. Advances have been achieved in discovering compounds with better activities and efforts have been made to understand the structure-activity relationships (SARs) of these NKT cell ligands. In this review, we discuss the structure modifications based on KRN7000, the principal glycolipid used in the study of NKT cell stimulation, and the SARs based on these modified structures.展开更多
Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type ...Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type calcium channels.T-type calcium channel blockers,such as pimozide and mibefradil,have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury.However,the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear.Here,in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons.The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons.We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury.Cav3.2 knockout markedly reduced infarct volume and brain water content,and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury.Additionally,Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress,inflammatory response,and neuronal apoptosis.In the hippocampus of Cav3.2-knockout mice,calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury.These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling.Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.展开更多
文摘Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells play a role in many events that require urgent intervention,especially anaphylaxis,has led to a more detailed study of these cells.The diseases also caused by dysfunctions of mast cells have been examined in many circumstances.For instance,mast cell activation syndrome is known as an augmented number of cells due to decreased cell death,resulting in clinical symptoms affecting many systems.The main common symptoms include flushing,hypotension,urticaria,angioedema,headache,vomiting and diarrhea.Although the underlying mechanism is not yet clearly known,we aim to review the literature in a broad perspective and bring together the existing knowledge in the light of the literature due to the diversity of its involvement in the body and the fact that it is a little known syndrome.
基金Acknowledgments We thank Drs Hua Gu (Columbia University, USA), Weiguo Zhang (Duke University Medical Center, USA), and Youhai H Chen (University of Pennsylvania, USA) for reviewing the manuscript and for suggestions, and Dr Ilia Voskoboinik (Peter MacCallum Cancer Centre, Australia) for providing the mouse perforin cDNA in pKS(+) Bluescript. Ragl^-/- mice were gifts from Xiaolong Liu (Shanghai Institutes for Biological Sciences, China). This work was supported by grants from the National Natural Science Foundation of China (30325018, 30530700, 30623003, and 30421005) and CAS project (KSCX1-YW-R-43), grants from the National Key Project 973 (2006CB504300 and 2007CB512404), grants from the Technology Commission of Shanghai Municipality (04DZ14902, 04DZ19108, 06DZ22032, 04DZ19112, 07XD14033, and 07DZ22916), 863 key project (2006AA02A247), and a grant from the E-institutes of Shanghai Universities Immunology Division.
文摘Perforin is a pore-forming protein engaged mainly in mediating target T cell death and is employed by cytotoxic T lymphocytes (CTLs) and natural killer cells. However, whether it also plays a role in conventional CD4^+ T cell function remains unclear. Here we report that in perforin-deficient (PKO) mice, CD4^+ T cells are hyperproliferative in response to T cell receptor (TCR) stimulation. This feature of hyperproliferation is accompanied by the enhancement both in cell division and in IL-2 secretion. It seems that the perforin deficiency does not influence T cell development in thymus spleen and lymph node. In vivo, perforin deficiency results in increased antigen-specific T cell proliferation and antibody production. Furthermore, PKO mice are more susceptible to experimental autoimmune uveitis. To address the molecular mechanism, we found that after TCR stimulation, CD4^+ T cells from PKO mice display an increased intracellular calcium flux and subsequently enhance activation of transcription factor NFAT1. Our results indicate that perforin plays a negative role in regulating CD4^+ T cell activation and immune response by affecting TCR-dependent Ca^2+ signaling.
基金Supported by Sao Paulo Research Public Foundation FAPESPNational Counsel of Technological and Scientific Development CNPq,No.07/07193-3 and No.12/02270-2
文摘Mesenchymal stromal cells(MSCs) possess great therapeutic advantages due to their ability to produce a diverse array of trophic/growth factors related to cytoprotection and immunoregulation.MSC activation via specific receptors is a crucial event for these cells to exert their immunosuppressive response.The aryl-hydrocarbon receptor(Ah R) is a sensitive molecule for external signals and it is expressed in MSCs and,upon positive activation,may potentially regulate the MSC-associated immunomodulatory function.Consequently,signalling pathways linked to Ah R activation can elucidate some of the molecular cascades involved in MSC-mediated immunosuppression.In this minireview,we have noted some important findings concerning MSC regulation via Ah R,highlighting that its activation is associated with improvement in migration and immunoregulation,as well as an increase in pro-regenerative potential.Thus,Ah R-mediated MSC activation can contribute to new perspectives on MSC-based therapies,particularly those directed at immune-associated disorders.
文摘This paper described T cell proliferative response by an alternative pathway in normal subjects and In patients with malignant diseases. Two McAbs, Anti-CCTl and Lo-CD2-act recognizing two distinct epitopes on E-receptor (CD2) were used to costimulate PBMC. Proliferative responsiveness was measured by 3H-thymidine incorporation. It was found that 82% of 72 nonnal subjects gave proliferative response whereas only 23% of the 93 patients did. The average cpm±SD in patients with bladder cancer (118±2314), kidney cancer (1619±2719) or lymphoma (2518±4057) was significantly lower than that in normal subjects (4935±2314), (P<0.001). These results indicate that T cell proliferation through the alternative pathway was significantly depressed in patients with cancer, and this can be used as a new parameter to monitor the immune status of cancer patients.
基金supported in part by the Department of Anesthesiology and Pain Medicine of University of California Davis Health and NIH grant UL1TR000002 to the University of California Davis Health
文摘Mast cell activation syndrome(MCAS)includes a group of disorders that result in the inappropriate release of inflammatory mediators from mast cells.These mediators can affect multiple organ systems and lead to significant morbidity,and possible fatality.Although reactions,typically in response to various nonspecific stimuli,are usually mild,they may put those with MCAS at increased risk of anaphylaxis.In this case report,we present two clinical scenarios of MCAS,and identify possible factors triggering mast cell mediator release.We also define a preoperative preventive pathway,outline anesthetic considerations,and discuss the management of immediate hypersensitivity reactions in patients with MCAS.Meticulous preoperative preparation,avoidance of triggers,and development of a plan to treat possible adverse organ responses are paramount of good outcomes.
文摘To investigate whether estradiol (E2) plays a role in cell-contact-dependent regulatory mechanism of T cell activation, we studied the role of E2 in regulating gene transcription of CTLA-4, ICOS, B7-1, B7-2 and B7h in vitro. The splenic cells of normal female BALB/c mice were activated by ConA. Then the cells were cultured with E2 (100 pg/ml or 50 ng/ml) for 24 h or 48 h, respectively. The cell proliferation was measured by MTF assay and the expression of the co-stimulatory molecules mRNA was examined by RT-PCR analysis. We found that E2 (100 pg/ml, physiological level) stimulated the acti- vated spleen cells proliferation; inhibited CTLA-4, ICOS, TGF-β and IL-10 gene transcription; promoted B7-1 and B7-2 gene transcription. E2 (50 ng/ml, pregnant level) inhibited the proliferation of the activated splenic cells; promoted CTLA-4, B7-1, IL-10 but inhibited B7-2 and TGF-β gene transcription. Therefore, we conclude that the effects of E2 on T cell activation are partially through its regulation on the co-stimulatory molecules. The co-stimulatory molecules are crucial components of the cell-contact dependent regulatory mechanism, and E2 may regulate T cell activation by this mechanism.
基金supported by the National Research Programs from the Ministry of Science and Technology of China(grant no.2021YFF0701800)the National Natural Science Foundation of China(grant nos.52032008 and 22277071)+1 种基金the Collaborative Innovation Center of Suzhou Nano Science and Technologythe“111”program from the Ministry of Education of China.
文摘The spatial arrangement of activating ligands is known to have great influence on T cell activation.However,independently studying each ligand’s spatial organization parameter that affects T cell activation remains a great challenge.Here,with DNA origami,we precisely organized the CD3ɛantibodies simulating T cell receptor(TCR)ligands and CD28 antibodies simulating co-stimulatory ligands to interrogate the independent role of TCR-ligand spacing and local copy numbers as well as the spacing between TCR ligands and co-stimulatory ligands on T cell activation.We found that T cell activation benefited fromlocally concentrated TCR ligands with a shorter spacing and was maximized by an∼38 nm spacing between TCR ligands and co-stimulatory ligands.The T cell expander constructed based on our findings could efficiently expand CD8+T cells for tumor immunotherapy.Thus,the DNA nanostructurebased ligands’precise arrangement can be a unique tool in studying immune cell activations and cellbased immunotherapies.
基金Partially supported by the National Natural Science Foundation of China(81373465)
文摘Abstract The lipids present in hepatic stellate cells (HSCs) lipid droplets include retinyl ester, triglyceride, cholesteryl ester, cholesterol, phospholipids and free fatty acids. Activation of HSCs is crucial to the development of fibrosis in liver disease. During activation, HSCs transform into myofibroblasts with concomitant loss of their lipid droplets and production of excessive extracellular matrix. Release of lipid droplets containing retinyl esters and triglyceride is a defining feature of activated HSCs. Accumulating evidence supports the proposal that recovering the accumulation of lipids would inhibit the activation of HSCs. In healthy liver, quiescent HSCs store 80% of total liver retinols and release them depending on the extracellular retinol status. However, in injured liver activated HSCs lose their retinols and produce a considerable amount of extracelhilar matrix, subsequently leading to liver fibrosis. Further findings prove that lipid metabolism of HSCs is closely associated with its activation, yet relationship between activated HSCs and the lipid metabolism has remained mysterious.
基金supported by Saving Sight in Grampian and the Development Trust of the University of Aberdeen。
文摘Dendritic cells(DC)are the major antigen-presenting cells bridging innate and adaptive immunity,a function they perform by converting quiescent DC to active,mature DC with the capacity to activate naı¨ve T cells.They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues.Here,wedemonstrate thatmyeloid cell-specific genetic deletion of PTP1B(LysM PTP1B)leads to defects in lipopolysaccharide-driven bone marrow-derivedDC(BMDC)activation associated with increased levels of phosphorylated Stat3.We showthatmyeloid cell-specific PTP1Bdeletion also causes decreased migratory capacity of epidermal DC,aswell as reduced CCR7 expression and chemotaxis to CCL19 by BMDC.PTP1B deficiency in BMDC also impairs their migration in vivo.Further,immature LysM PTP1B BMDC display fewer podosomes,increased levels of phosphorylated Src at tyrosine 527,and loss of Src localization to podosome puncta.In co-culture with T cells,LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC.Finally,LysMPTP1BBMDCfail to present antigen to T cells as efficiently as controlBMDC.These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation.
基金Foundation item: the National Natural Science Foundation (No. 30430630)
文摘Adapter proteins can regulate the gene transcriptions in disparate signaling pathway by interacting with multiple signaling molecules, including T cell activation signaling. Nuclear receptor binding protein (NRBP), a novel adapter protein, represents a small family of evolutionarily conserved proteins with homologs in Caenorhabditis elegans (C. elegans), Drosophila melanogaster (i). melanogaster), mouse and human. Here, we demonstrated that overexpression of NRBP in Jurkat TAg cells specifically impairs T cell receptor (TCR) or phorbol myristate acetate (PMA) /ionomycin-mediated signaling leading to nuclear factor of activated T cells (NFAT) promoter activation. Furthermore, the N-terminal of NRBP is necessary for its regulation of NFAT activation. Finally, we showed that NRBP has minimal effect on both TCR- and PMA-induced CD69 up-regulation in Jurkat TAg cells, which suggests that NRBP may function downstream of protein kinase C (PKC) /Ras pathway.
基金Supported by the Scientific Development Programs of Science and Technology Commission Foundation of Shanghai (004119047).
文摘Objective To investigate the relationship between expression of somatostatin receptors(SSTRs) and activation of rat hepatic stellate cell (HSC). Methods HSCs were isolated from rats by in situ perfusion and single-step density gradient centrifugation, and then SSTR1-5 mRNA levels in the differentiated first passage HSCs were detected by means of reverse transcription polymerase chain reaction. On the other hand, hepatic fibrosis was induced in adult male Sprague-Dawley rats by carbon tetrachloride intoxication, and the expression of SSTR1-5 in normal as well as fibrotic liver was measured by immunohistochemical staining. Results SSTR mR-NA and SSTR could not be found in freshly isolated rat HSCs and normal rat liver. But SSTR1-3 mRNA appeared as HSCs became wholly activated, and SSTR1-3 could also be identified on the membrane of activated HSCs in the peri-sinusoid space, fibrous septa, etc. Conclusion The expression of SSTR1-3 in the rat HSC is closely related to its activation. This may reflect one of the main negative regulation mechanisms in the course of HSC activation.
基金supported by grants from the Canadian Institutes of Health Research(CIHR)MT-14429,MOP-82906,and FDN-143338 to A.V.NSFC-31870863 from the National Natural Science Foundation of China to N.W.supported by a Postdoctoral Fellowship from Fonds de recherche du Quebec Santr(FRQS)。
文摘One of the hallmarks of live cells is the asymmetric distribution of lipids across their plasma membrane.Changes in this asymmetry due to lipid"scrambling"result in phosphatidylserine exposure at the cell surface that is detected by annexin V staining.This alteration is observed during cell death processes such as apoptosis,and during physiological responses such as platelet degranulation and membrane repair.Previous studies have shown that activation of NK cells is accompanied by exposure of phosphatidylserine at the cell surface.While this response was thought to be indicative of ongoing NK cell death,it may also reflect the regulation of NK cell activation in the absence of cell death.Herein,we found that NK cell activation was accompanied by rapid phosphatidylserine exposure to an extent proportional to the degree of NK cell activation.Through enforced expression of a lipid scramblase,we provided evidence that activation-induced lipid scrambling in NK cells is reversible and does not lead to cell death.In contrast,lipid scrambling attenuates NKcell activation.This response was accompanied by reduced cell surface expression of activating receptors such as 2B4,and by loss of binding of Src family protein tyrosine kinases Fyn and Lck to the inner leaflet of the plasma membrane.Hence,lipid scrambling during NK cell activation is,at least in part,a physiological response that reduces the NK cell activation level.This effect is due to the ability of lipid scrambling to alter the distribution of membrane-associated receptors and kinases required for NK cell activation.
文摘Objective To investigate the expression of B cell activation factor of the TNF family (BAFF) gene between human normal and inflamed fallopian tubes. Methods Tissue samples of human normal fallopian tube (n=20) and inflamed fallopian tube (n=20) were collected. The expression of BAFF gene was determined by the real- time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Results BAFF immunostaining appeared on the cellular membrane and in the cytoplasm of tubal epithelial cells. Both BAFF protein and mRNA in normal fallopian tubes had lower levels than those in inflamed fallopian tubes (P〈0.01). Conclusion BAFF protein and mRNA are present in human tubal tissues. BAFF gene in human inflamed fallopian tube would have a high expression.
文摘Gelatinase A (MMP-2) is considered to play a critical role in cell migration and invasion. The proteinase is secreted from the cell as an inactive zymogen. In vivo it is postulated that activation of progelationase A (proMMP-2) takes place on the cell surface mediated by membrane-type matrix metalloproteinases (MT-MMPs). Recent studies have demonstrated that proMMP-2 is recruited to the cell surface by interacting with tissue inhibitor of metalloproteinases-2 (TIMP-2) bound to MT1MMP by forming a ternary complex. bee MT1-MMP closely located to the ternary complex then activates proMMP-2 on the cell surface. MT1-MMP is found in cultured invasive cancer cells at the invadopodia. The MTMMP/TIMP-2/ MMP- 2 system t bus provides localized expression of proteolysis of the extracellular matrix required for cell migration.
基金a grant from Chang Gung Memorial Hospital,No.CMRPG33074a grant from National Science Council,Taiwan
文摘AIM:To investigate the role of nuclear factor of activated T cell 2(NFAT2),the major NFAT protein in peripheral T cells,in sustained T cell activation and intractable inflammation in human ulcerative colitis(UC). METHODS:We used two-dimensional gel-electrophoresis, immunohistochemistry,double immunohistochemical staining,and confocal microscopy to inspect the expression of NFAT2 in 107,15,48 and 5 cases of UC, Crohn's disease(CD),non-specific colitis,and 5 healthy individuals,respectively. RESULTS:Up-regulation with profound nucleo- translocation/activation of NFAT2 of lamina propria mononuclear cells(LPMC)of colonic mucosa was found specifically in the affected colonic mucosa from patients with UC,as compared to CD or NC(P<0.001,Kruskal- Wallis test).Nucleo-translocation/activation of NFAT2 primarily occurred in CD8+T,but was less prominent in CD4+T cells or CD20+B cells.It was strongly associated with the disease activity,including endoscopic stage (τ=0.2145,P=0.0281)and histologic grade(τ=0.4167, P<0.001). CONCLUSION:We disclose for the first time the nucleo-translocation/activatin of NFAT2 in lamina propria mononuclear cells in ulcerative colitis.Activation of NFAT2 was specific for ulcerative colitis and highly associated with disease activity.Since activation of NFAT2is implicated in an auto-regulatory positive feedback loop of sustained T-cell activation and NFAT proteins play key roles in the calcium/calcineurin signaling pathways,our results not only provide new insights into the mechanism for sustained intractable inflammation,but also suggest the calcium-calcineurin/NFAT pathway as a new therapeutic target for ulcerative colitis.
基金this work was supported by Xi'an Science and technology Research Fund (GG04134)
文摘Objective To explore the correlation between endothelia cells activation and cytokines (ET-1, NO) levels in patients with pulmonary hypertension (PH), and to discuss their roles in the development of PH. Methods Twenty patients with simple ventricular septal defect (VSD) were chosen as controls, and 30 patients with PH were studied. Plasma levels of ET-1 and NO were measured by radioimmunoassay or colorimetric method. Before cardiopulmonary bypass was established, the specimens from right lung were fixed with formaldehyde solution, embedded with paraffin and stained by SP immunohistochemistry. Intercellular adhesion molecule-1 (ICAM-1) expression was measured through the determination of the light density with computer imaging technology. Results Compared with that of the patients with simple VSD, the light density of ICAM-1 and plasma level of ET-1 increased in patients with PH; but plasma level of NO decreased (P<0.05). Positive correlation was observed between ICAM-1 and ET-1/NO (P<0.05). Conclusion Endothelia cells activation and imbalance of ET-1/NO might play an important role in the development of PH.
基金This work was supported by the Ministry of Education,Science and Technological Development of The Republic of Serbia(Contract No.451-03-68/2022-14/200135).
文摘A key feature that distinguishes cancer cells from all other cells is their capability to spread throughout the body.Although how cancer cells collectively migrate by following molecular rules which influence the state of cell-cell adhesion contacts has been comprehensively formulated,the impact of physical interactions on cell spreading remains less understood.Cumulative effects of physical interactions exist as the interplay between various physical parameters such as(1)tissue surface tension,(2)viscoelasticity caused by collective cell migration,and(3)solid stress accumulated in the cell aggregate core region.This review aims to point out the role of these physical parameters in cancer cell spreading by considering and comparing the rearrangement of various mono-cultured cancer and epithelial model systems such as the fusion of two cell aggregates.While epithelial cells undergo volumetric cell rearrangement driven by the tissue surface tension,which directs cell movement from the surface to the core region of two-aggregate systems,cancer cells rather perform surface cell rearrangement.Cancer cells migrate toward the surface of the two-aggregate system driven by the solid stress while the surface tension is significantly reduced.The solid stress,accumulated in the core region of the two-aggregate system,is capable of suppressing the movement of epithelial cells that can undergo the jamming state transition;however,this stress enhances the movement of cancer cells.We have focused here on the multi-scale rheological modeling approaches that aimed at reproducing and understanding these biological systems.
基金National Natural Science Foundation of China (Grant No.90713010)"863"Program from the Ministry of Science and Technology of China (Grant No.2006AA09Z405).
文摘α-Galactosylceramides, which can be recognized by natural killer T (NKT) cells, are now attracting more and more attention due to their therapeutic potential in cancer, infection and autoimmune diseases. Advances have been achieved in discovering compounds with better activities and efforts have been made to understand the structure-activity relationships (SARs) of these NKT cell ligands. In this review, we discuss the structure modifications based on KRN7000, the principal glycolipid used in the study of NKT cell stimulation, and the SARs based on these modified structures.
基金supported by the Natural Science Foundation of Anhui Province of China,No.2208085Y32Scientific Research Plan Project of Anhui Province of China,No.2022AH020076the Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province,No.CXPJJH12000005-07-115(all to CT).
文摘Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type calcium channels.T-type calcium channel blockers,such as pimozide and mibefradil,have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury.However,the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear.Here,in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons.The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons.We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury.Cav3.2 knockout markedly reduced infarct volume and brain water content,and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury.Additionally,Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress,inflammatory response,and neuronal apoptosis.In the hippocampus of Cav3.2-knockout mice,calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury.These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling.Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.