AIM: Persistent hepatitis B virus (HBV) infection is characterized by a weak CD8+ T cell response to HBV. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may facilitate viral ...AIM: Persistent hepatitis B virus (HBV) infection is characterized by a weak CD8+ T cell response to HBV. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may facilitate viral clearance in chronically infected individuals. Therefore, we examined whether CD25+CD4+ regulatory T (Treg) cells might be involved in a inhibition of CD8+T cell priming or in the modulation of the magnitude of the 'peak' antiviral CD8+ T cell response primed by DNA immunization. METHODS: B10.D2 mice were immunized once with plasmid pCMV-S. Mice received 500 μg of anti-CD25 mAb injected intraperitoneally 3 d before DNA immunization to deplete CD25+ cells. Induction of HBV-specific CD8+ T cells in peripheral blood mononuclear cells (PBMCs) was measured by S28-39 peptide loaded DimerX staining and their function was analyzed by intracellular IFN-γ staining. RESULTS: DNA immunization induced HBV-specific CD8+ T cells. At the peak T cell response (d 10), 7.1±2.0% of CD8+ T cells were HBV-specific after DNA immunization, whereas 12.7±3.2% of CD8+ T cells were HBV-specific in Treg-depleted mice, suggesting that DNA immunization induced more antigen-specific CD8+ T cells in the absence of CD25+ Treg cells (n = 6, P<0.05). Similarly, fewer HBV specific memory T cells were detected in the presence of these cells (1.3±0.4%) in comparison to Treg-depleted mice (2.6±0.9%) on d 30 after DNA immunization (n - 6, P<0.01). Both IFN-γ production and the avidity of the HBV-specific CD8+ T cell response to antigen were higher in HBV-specific CD8+ T cells induced in the absence of Treg cells. CONCLUSION: CD25+ Treg cells suppress priming and/or expansion of antigen-specific CD8+ T cells during DNA immunization and the peak CD8+ T cell response is enhanced by depleting this cell population. Furthermore, Treg cells appear to be involved in the contraction phase of the CD8+ T cell response and may affect the quality of memory T cell pools. The elimination of Treg cells or their inhibition may be important in immunot展开更多
AIM: To investigated the interaction between toll-like receptor 4 (TLR4)-activated hepatoma cells and macrophages in the induction of tumor-immune suppression mediated by CD4+CD25high family of transcription factor P3...AIM: To investigated the interaction between toll-like receptor 4 (TLR4)-activated hepatoma cells and macrophages in the induction of tumor-immune suppression mediated by CD4+CD25high family of transcription factor P3 (FOXP3) regulatory T cells (Tregs). METHODS: The proportion of FOXP3+ Tregs was identified in peripheral blood and tumor tissues of 60 hepatocellular carcinoma (HCC) patients. TLR4 expression was examined in tumor tissues and cell lines. The correlation was examined between FOXP3+ Tregs in peripheral blood and TLR4 expression of HCC tissues. Following activation of TLR4 in H22 murine hepatoma cells pre-incubated with lipopolysaccharide (LPS) and co-cultured with macrophage cell line RAW246.7, the synthesis of cytokines tumor necrosis factor-α, CCL22, and interleukin (IL)-10 by the two cell lines was detected and analyzed. RESULTS: FOXP3+ Tregs were enriched in tumor sites, and circulating FOXP3+ Tregs were increased in HCC patients in correlation with multiple tumor foci and up-regulated TLR4 expression in HCC tissues. Semi-quantitative analysis indicated that TLR4 was over-expressed in HCC compared with the matched normal tissues. Cell cultivation experiments indicated that the mRNAs of IL-10 and CCL22 were significantly up-regulated in the RAW246.7 cell line when co-cultured with LPS preincubated H22 cells. CONCLUSION: In hepatoma cell lines, TLR4 may indirectly facilitate the recruitment of Tregs to the tumor site and promote intrahepatic metastasis through its interaction with macrophages.展开更多
Balanced immunity is pivotal for health and homeostasis.CD4+helper T(Th)cells are central to the balance between immune tolerance and immune rejection.Th cells adopt distinct functions to maintain tolerance and clear ...Balanced immunity is pivotal for health and homeostasis.CD4+helper T(Th)cells are central to the balance between immune tolerance and immune rejection.Th cells adopt distinct functions to maintain tolerance and clear pathogens.Dysregulation of Th cell function often leads to maladies,including autoimmunity,inflammatory disease,cancer,and infection.Regulatory T(Treg)and Th17 cells are critical Th cell types involved in immune tolerance,homeostasis,pathogenicity,and pathogen clearance.It is therefore critical to understand how Treg and Th17 cells are regulated in health and disease.Cytokines are instrumental in directing Treg and Th17 cell function.The evolutionarily conserved TGF-β(transforming growth factor-β)cytokine superfamily is of particular interest because it is central to the biology of both Treg cells that are predominantly immunosuppressive and Th17 cells that can be proinflammatory,pathogenic,and immune regulatory.How TGF-βsuperfamily members and their intricate signaling pathways regulate Treg and Th17 cell function is a question that has been intensely investigated for two decades.Here,we introduce the fundamental biology of TGF-βsuperfamily signaling,Treg cells,and Th17 cells and discuss in detail how the TGF-βsuperfamily contributes to Treg and Th17 cell biology through complex yet ordered and cooperative signaling networks.展开更多
The aim of this study was to explore the effects of varicocele on the morphology and function of Leydig cells in the rat testis. Forty male Sprague-Dawley rats were divided into two groups： the experimental group und...The aim of this study was to explore the effects of varicocele on the morphology and function of Leydig cells in the rat testis. Forty male Sprague-Dawley rats were divided into two groups： the experimental group underwent surgery to create a left varicocele （VC）, and the control group underwent a sham operation. Serum testosterone and intratesticular testosterone levels were measured using a radioimmunoassay after 4 and 8 weeks of operation. Leydig cells were studied for apoptosis and expression of steroidogenetic acute regulatory （STAR） protein mRNA levels. Serum testosterone levels declined after 4 and 8 weeks of operation but were not significant （P〉0.05）. However, the intratesticular testosterone levels after 8 weeks were significantly decreased compared with the control group （P〈0.01）. The mean apoptosis index of Leydig cells in the experimental group was significantly higher than that in the control group after 4 or 8 weeks （P〈0.01）. StAR mRNA levels in the Leydig cells of the experimental group were significantly lower compared to those of the control group （P〈0.01）. Our data show that varicocele did impair Leydig cell function by increasing apoptosis and suppressing the expression of the StAR protein.展开更多
Asthma is a chronic disease of airway inflammation due to excessive T helper cell type 2 （Th2） response. Present treatment based on inhalation of synthetic glucocorticoids can only control Th2-driven chronic eosinop...Asthma is a chronic disease of airway inflammation due to excessive T helper cell type 2 （Th2） response. Present treatment based on inhalation of synthetic glucocorticoids can only control Th2-driven chronic eosinophilic inflammation, but cannot change the immune tolerance of the body to external allergens. Regulatory T cells （Tregs） are the main negative regulatory cells of the immune response. Tregs play a great role in regulating allergic, auto- immune, graft-versus-host responses, and other immune responses. In this review, we will discuss the classification and biological characteristics, the established immunomodulatory mechanisms, and the characteristics of induced differentiation of Tregs. We will also discuss the progress of TregS in the field of asthma. We believe that further studies on the regulatory mechanisms of Tregs will provide better treatments and control strategies for asthma.展开更多
Background： Regulatory T-cells （Treg） play key roles in suppressing cell-mediated immunity in cancer patients. Little is known about perioperative Treg fluctuations in nonsmall cell lung cancer （NSCLC）. Video-ass...Background： Regulatory T-cells （Treg） play key roles in suppressing cell-mediated immunity in cancer patients. Little is known about perioperative Treg fluctuations in nonsmall cell lung cancer （NSCLC）. Video-assisted thoracoscopic （VATS） lobectomy, as a minimal invasive procedure for treating NSCLC, may have relatively less impact on the patient＇s immune system. This study aimed to observe perioperative dynamics of circulating Treg and natural killer （NK） cell levels in NSCLC patients who underwent major Iobectomy by VATS or thoracotomy. Methods： Totally, 98 consecutive patients with stage I NSCLC were recruited and assigned into VATS or thoracotomy groups. Peripheral blood samples were taken on 1-day prior to operation, postoperative days （PODs） I, 3, 7, 30, and 90. Circulating Treg and NK cell counts were assayed by flow cytometry, defined as CD4＋CD25＋CD127w cells in CD4＋ lymphocytes and CD56＋I6＋CD3 cells within CD45＋ leukocytes respectively. With SPSS software version 21.0 （SPSS Inc., USA）, differences between VATS and thoracotomy groups were determined by one-way analysis of variance （ANOVA）, and differences between preoperative baseline and PODs in each group were evaluated by one-way ANOVA Dunnett t-test. Results： In both groups, postoperative Treg percentages were lower than preoperative status. No statistical difference was found between VATS and thoracotomy groups on PODs 1, 3, 7, and 30. On POD 90, Treg percentage in VATS group was significantly lower than in thoracotomy group （5.26 ± 2.75 vs. 6.99 ±3.60, P = 0.012）. However, a higher level of NK was found on all PODs except on POD 90 in VATS group, comparing to thoracotomy group. Conclusions： Lower Treg level on POD 90 and higher NK levels on PODs 1, 3, 7, 30 in VATS group might imply better preserved cell-mediated immune function in NSCLC patients, than those in thoracotomy group.展开更多
Hypoxic-ischemic brain damage(HIBD)is a common cause of infant death.The purpose of our research was to explore the immunoregulatory mechanism of placenta-derived mesenchymal stem cells(PD-MSCs)in HIBD treatment.Seven...Hypoxic-ischemic brain damage(HIBD)is a common cause of infant death.The purpose of our research was to explore the immunoregulatory mechanism of placenta-derived mesenchymal stem cells(PD-MSCs)in HIBD treatment.Seven-day-old rat pups were randomly divided into HIBD,PD-MSC,fibroblast,and control groups.Forty-eight hours after HIBD induction,cells at a density of 5×104 cells/10µl were injected into the cerebral tissue in the PD-MSC and fibroblast groups.The TNF-α,interleukin-17(IL-17),interferon-γ(IFN-γ),and IL-10 levels were detected through quantitative real-time polymerase chain reaction(RT-PCR)and enzyme-linked immunosorbent assay(ELISA).Regulatory T cell(Tregs)populations were detected through flow cytometry,and forkhead box P3(Foxp3)was measured through western blot analysis.Behavioral tests and gross and pathological examinations showed that PD-MSC treatment exerted significantly stronger neuroprotective effects than the other treatments.The expression levels of pro-inflammatory cytokines were substantially upregulated after HI injury.Compared with fibroblast treatment,PD-MSC treatment inhibited the production of pro-inflammatory cytokines and increased the production of IL-10 in the ischemic hemispheres and peripheral blood serum(all P<0.01).Flow cytometry results showed a notable increase in the number of Tregs within the spleen of the HIBD group.Moreover,the number of Tregs and the Foxp3 expression levels were higher in the PD-MSC treatment group than in the HIBD and fibroblast groups(all P<0.01).Our research suggests that the mechanism of PD-MSC treatment for HIBD partially involves inflammatory response suppression.展开更多
基金Supported by in part Grant-in-Aid for Scientific Research (C) (toK.K)
文摘AIM: Persistent hepatitis B virus (HBV) infection is characterized by a weak CD8+ T cell response to HBV. Immunotherapeutic strategies that overcome tolerance and boost these suboptimal responses may facilitate viral clearance in chronically infected individuals. Therefore, we examined whether CD25+CD4+ regulatory T (Treg) cells might be involved in a inhibition of CD8+T cell priming or in the modulation of the magnitude of the 'peak' antiviral CD8+ T cell response primed by DNA immunization. METHODS: B10.D2 mice were immunized once with plasmid pCMV-S. Mice received 500 μg of anti-CD25 mAb injected intraperitoneally 3 d before DNA immunization to deplete CD25+ cells. Induction of HBV-specific CD8+ T cells in peripheral blood mononuclear cells (PBMCs) was measured by S28-39 peptide loaded DimerX staining and their function was analyzed by intracellular IFN-γ staining. RESULTS: DNA immunization induced HBV-specific CD8+ T cells. At the peak T cell response (d 10), 7.1±2.0% of CD8+ T cells were HBV-specific after DNA immunization, whereas 12.7±3.2% of CD8+ T cells were HBV-specific in Treg-depleted mice, suggesting that DNA immunization induced more antigen-specific CD8+ T cells in the absence of CD25+ Treg cells (n = 6, P<0.05). Similarly, fewer HBV specific memory T cells were detected in the presence of these cells (1.3±0.4%) in comparison to Treg-depleted mice (2.6±0.9%) on d 30 after DNA immunization (n - 6, P<0.01). Both IFN-γ production and the avidity of the HBV-specific CD8+ T cell response to antigen were higher in HBV-specific CD8+ T cells induced in the absence of Treg cells. CONCLUSION: CD25+ Treg cells suppress priming and/or expansion of antigen-specific CD8+ T cells during DNA immunization and the peak CD8+ T cell response is enhanced by depleting this cell population. Furthermore, Treg cells appear to be involved in the contraction phase of the CD8+ T cell response and may affect the quality of memory T cell pools. The elimination of Treg cells or their inhibition may be important in immunot
文摘AIM: To investigated the interaction between toll-like receptor 4 (TLR4)-activated hepatoma cells and macrophages in the induction of tumor-immune suppression mediated by CD4+CD25high family of transcription factor P3 (FOXP3) regulatory T cells (Tregs). METHODS: The proportion of FOXP3+ Tregs was identified in peripheral blood and tumor tissues of 60 hepatocellular carcinoma (HCC) patients. TLR4 expression was examined in tumor tissues and cell lines. The correlation was examined between FOXP3+ Tregs in peripheral blood and TLR4 expression of HCC tissues. Following activation of TLR4 in H22 murine hepatoma cells pre-incubated with lipopolysaccharide (LPS) and co-cultured with macrophage cell line RAW246.7, the synthesis of cytokines tumor necrosis factor-α, CCL22, and interleukin (IL)-10 by the two cell lines was detected and analyzed. RESULTS: FOXP3+ Tregs were enriched in tumor sites, and circulating FOXP3+ Tregs were increased in HCC patients in correlation with multiple tumor foci and up-regulated TLR4 expression in HCC tissues. Semi-quantitative analysis indicated that TLR4 was over-expressed in HCC compared with the matched normal tissues. Cell cultivation experiments indicated that the mRNAs of IL-10 and CCL22 were significantly up-regulated in the RAW246.7 cell line when co-cultured with LPS preincubated H22 cells. CONCLUSION: In hepatoma cell lines, TLR4 may indirectly facilitate the recruitment of Tregs to the tumor site and promote intrahepatic metastasis through its interaction with macrophages.
基金This work was supported by the NIH(R01 AI160774,R01 AI123193,and R56 AG071256)the National Multiple Sclerosis Society(RG-1802-30483 to YYW)The figures were created using BioRender.com.
文摘Balanced immunity is pivotal for health and homeostasis.CD4+helper T(Th)cells are central to the balance between immune tolerance and immune rejection.Th cells adopt distinct functions to maintain tolerance and clear pathogens.Dysregulation of Th cell function often leads to maladies,including autoimmunity,inflammatory disease,cancer,and infection.Regulatory T(Treg)and Th17 cells are critical Th cell types involved in immune tolerance,homeostasis,pathogenicity,and pathogen clearance.It is therefore critical to understand how Treg and Th17 cells are regulated in health and disease.Cytokines are instrumental in directing Treg and Th17 cell function.The evolutionarily conserved TGF-β(transforming growth factor-β)cytokine superfamily is of particular interest because it is central to the biology of both Treg cells that are predominantly immunosuppressive and Th17 cells that can be proinflammatory,pathogenic,and immune regulatory.How TGF-βsuperfamily members and their intricate signaling pathways regulate Treg and Th17 cell function is a question that has been intensely investigated for two decades.Here,we introduce the fundamental biology of TGF-βsuperfamily signaling,Treg cells,and Th17 cells and discuss in detail how the TGF-βsuperfamily contributes to Treg and Th17 cell biology through complex yet ordered and cooperative signaling networks.
文摘The aim of this study was to explore the effects of varicocele on the morphology and function of Leydig cells in the rat testis. Forty male Sprague-Dawley rats were divided into two groups： the experimental group underwent surgery to create a left varicocele （VC）, and the control group underwent a sham operation. Serum testosterone and intratesticular testosterone levels were measured using a radioimmunoassay after 4 and 8 weeks of operation. Leydig cells were studied for apoptosis and expression of steroidogenetic acute regulatory （STAR） protein mRNA levels. Serum testosterone levels declined after 4 and 8 weeks of operation but were not significant （P〉0.05）. However, the intratesticular testosterone levels after 8 weeks were significantly decreased compared with the control group （P〈0.01）. The mean apoptosis index of Leydig cells in the experimental group was significantly higher than that in the control group after 4 or 8 weeks （P〈0.01）. StAR mRNA levels in the Leydig cells of the experimental group were significantly lower compared to those of the control group （P〈0.01）. Our data show that varicocele did impair Leydig cell function by increasing apoptosis and suppressing the expression of the StAR protein.
基金Zhejiang University and Springer-Vedag GmbH Germany, part of Springer Nature 2018
文摘Asthma is a chronic disease of airway inflammation due to excessive T helper cell type 2 （Th2） response. Present treatment based on inhalation of synthetic glucocorticoids can only control Th2-driven chronic eosinophilic inflammation, but cannot change the immune tolerance of the body to external allergens. Regulatory T cells （Tregs） are the main negative regulatory cells of the immune response. Tregs play a great role in regulating allergic, auto- immune, graft-versus-host responses, and other immune responses. In this review, we will discuss the classification and biological characteristics, the established immunomodulatory mechanisms, and the characteristics of induced differentiation of Tregs. We will also discuss the progress of TregS in the field of asthma. We believe that further studies on the regulatory mechanisms of Tregs will provide better treatments and control strategies for asthma.
文摘Background： Regulatory T-cells （Treg） play key roles in suppressing cell-mediated immunity in cancer patients. Little is known about perioperative Treg fluctuations in nonsmall cell lung cancer （NSCLC）. Video-assisted thoracoscopic （VATS） lobectomy, as a minimal invasive procedure for treating NSCLC, may have relatively less impact on the patient＇s immune system. This study aimed to observe perioperative dynamics of circulating Treg and natural killer （NK） cell levels in NSCLC patients who underwent major Iobectomy by VATS or thoracotomy. Methods： Totally, 98 consecutive patients with stage I NSCLC were recruited and assigned into VATS or thoracotomy groups. Peripheral blood samples were taken on 1-day prior to operation, postoperative days （PODs） I, 3, 7, 30, and 90. Circulating Treg and NK cell counts were assayed by flow cytometry, defined as CD4＋CD25＋CD127w cells in CD4＋ lymphocytes and CD56＋I6＋CD3 cells within CD45＋ leukocytes respectively. With SPSS software version 21.0 （SPSS Inc., USA）, differences between VATS and thoracotomy groups were determined by one-way analysis of variance （ANOVA）, and differences between preoperative baseline and PODs in each group were evaluated by one-way ANOVA Dunnett t-test. Results： In both groups, postoperative Treg percentages were lower than preoperative status. No statistical difference was found between VATS and thoracotomy groups on PODs 1, 3, 7, and 30. On POD 90, Treg percentage in VATS group was significantly lower than in thoracotomy group （5.26 ± 2.75 vs. 6.99 ±3.60, P = 0.012）. However, a higher level of NK was found on all PODs except on POD 90 in VATS group, comparing to thoracotomy group. Conclusions： Lower Treg level on POD 90 and higher NK levels on PODs 1, 3, 7, 30 in VATS group might imply better preserved cell-mediated immune function in NSCLC patients, than those in thoracotomy group.
基金supported by grants from the Dongying City Technology Development Project(Grant No.2011106).
文摘Hypoxic-ischemic brain damage(HIBD)is a common cause of infant death.The purpose of our research was to explore the immunoregulatory mechanism of placenta-derived mesenchymal stem cells(PD-MSCs)in HIBD treatment.Seven-day-old rat pups were randomly divided into HIBD,PD-MSC,fibroblast,and control groups.Forty-eight hours after HIBD induction,cells at a density of 5×104 cells/10µl were injected into the cerebral tissue in the PD-MSC and fibroblast groups.The TNF-α,interleukin-17(IL-17),interferon-γ(IFN-γ),and IL-10 levels were detected through quantitative real-time polymerase chain reaction(RT-PCR)and enzyme-linked immunosorbent assay(ELISA).Regulatory T cell(Tregs)populations were detected through flow cytometry,and forkhead box P3(Foxp3)was measured through western blot analysis.Behavioral tests and gross and pathological examinations showed that PD-MSC treatment exerted significantly stronger neuroprotective effects than the other treatments.The expression levels of pro-inflammatory cytokines were substantially upregulated after HI injury.Compared with fibroblast treatment,PD-MSC treatment inhibited the production of pro-inflammatory cytokines and increased the production of IL-10 in the ischemic hemispheres and peripheral blood serum(all P<0.01).Flow cytometry results showed a notable increase in the number of Tregs within the spleen of the HIBD group.Moreover,the number of Tregs and the Foxp3 expression levels were higher in the PD-MSC treatment group than in the HIBD and fibroblast groups(all P<0.01).Our research suggests that the mechanism of PD-MSC treatment for HIBD partially involves inflammatory response suppression.
