Naive CD4 T cells can differentiate into at least two different types ofT helpers, Thl and Th2 cells. Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathog...Naive CD4 T cells can differentiate into at least two different types ofT helpers, Thl and Th2 cells. Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathogens and in the induction of asthma and other allergic diseases. In this review, we summarize recent reports regarding the transcription factors involved in Th2 differentiation and cell expansion, including StatS, Gfi- 1 and GATA-3. Stats activation is necessary and sufficient for IL-2-mediated function in Th2 differentiation. Enhanced Stats signaling induces Th2 differentiation independent of IL-4 signaling; although it does not up-regulate GATA-3 expression, it does require the presence of GATA-3 for its action. Gfi-1, induced by IL-4, promotes the expansion of GATA-3-expressing cells. Analysis of conditional Gata3 knockout mice confirmed the critical role of GATA-3 in Th2 cell differentiation （both IL-4 dependent and IL-4 independent） and in Th2 cell proliferation and also showed the importance of basal GATA-3 expression in inhibiting Thl differentiation.展开更多
Upon antigen stimulation, naive T helper cells differentiate into distinct lineages to attain specialized properties and effector functions. TH17 cells, a recently identified lineage of CD4＋ effector T cells, play a ...Upon antigen stimulation, naive T helper cells differentiate into distinct lineages to attain specialized properties and effector functions. TH17 cells, a recently identified lineage of CD4＋ effector T cells, play a key role in the immune defense against fungi and extracellular bacteria, but also contribute to the pathogenesis of many autoimmune conditions. The differentiation of TH 17 cells is orchestrated by an intricate network of signaling pathways and transcriptional regulators in T cells. While the involvement of T cell-intrinsic pathways has been described extensively, we are just beginning to appreciate how TH17 cell development is shaped by extrinsic pathways, espec- ially the innate immune signals. Dendritic cells （DCs）, the most important cell type to bridge innate and adaptive immunity, drive TH17 cell differentiation by providing antigenic, costimulatory and cytokine signals. This is mediated by the recognition of innate and inflam- matory signals by DCs via pattern recognition receptors, cytokine receptors and other immunomodulatory receptors that in turn activate the intracellular signaling network. In particular, p38a MAP kinase has emerged as a critical pathway to program DC-dependent TH17 cell differentiation by integrating multiple instructive signals in DCs. Here, we summarize the current knowledge on the mechanisms by which DC-derived innate immune signals drive TH17 cell differentiation.展开更多
The programmed cell death-1(PD-1)/PD-ligand 1(PD-L1)pathway is critical for normal pregnancy by promoting regulatory T(Treg)cell development and inhibiting the Th17 response.However,the relationship between the PD-1/P...The programmed cell death-1(PD-1)/PD-ligand 1(PD-L1)pathway is critical for normal pregnancy by promoting regulatory T(Treg)cell development and inhibiting the Th17 response.However,the relationship between the PD-1/PD-L1 pathway and the Treg/Th17 imbalance in pre-eclampsia(PE)is an enigma.In this study,decreased PD-1 and PD-L1 expression and a Treg/Th17 imbalance were observed at the maternal-fetal interface in PE.The regulatory effects of the PD-1/PD-L1 pathway on the Treg and Th17 cell quantities were determined in vitro by targeting T-cell proliferation,differentiation and transdifferentiation.First,decreased PD-1 expression might contribute to a higher Th17 cell frequency by promoting proliferation in PE.Second,the percentages of Treg but not Th17 cells differentiated from peripheral naive CD4+T cells were increased by PD-L1 Fc administration.This effect was accompanied by decreased PI3K/AKT/m-TOR and increased PTEN mRNA expression and was completely reversed by PD-1 blockade.Finally,the percentage of IL-17-producing Treg cells increased and was positively associated with the Th17 cell frequency in PE.Increased RORγt and IL-17 but not Foxp3 and IL-10 mRNA expression by Treg cells was observed with PD-1 blockade.Similar findings occurred when Treg cells were exposed to IL-6/IL-23/IL-1βand were reversed by PD-L1 Fc.Taken together,our findings indicate that the PD-1/PD-L1 pathway contributes to the Treg/Th17 imbalance via‘one-two punch’approaches:(i)promoting Th17 cell proliferation,(ii)inhibiting Treg cell differentiation and(iii)enhancing Treg cell plasticity into Th17 cells in PE.The therapeutic value of PD-L1 Fc for PE treatment will be explored in the future.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
AIM To investigate T-cell activation, the percentage of peripheral T regulatory cells(Tregs), Th17 cells and the circulating cytokine profile in systemic sclerosis(SSc).METHODS We enrolled a total of 24 SSc patients a...AIM To investigate T-cell activation, the percentage of peripheral T regulatory cells(Tregs), Th17 cells and the circulating cytokine profile in systemic sclerosis(SSc).METHODS We enrolled a total of 24 SSc patients and 16 healthy controls in the study and divided the patients as having diffuse cutaneous SSc(dc SSc, n = 13) or limited cutaneous SSc(lc SSc, n = 11). We performed a further subdivision of the patients regarding the stage of the disease-early, intermediate or late. Peripheral venous blood samples were collected from all subjects. We performed flow cytometric analysis of the activationcapacity of T-lymphocytes upon stimulation with PHA-M and of the percentage of peripheral Tregs and Th17 cells in both patients and healthy controls. We used ELISA to quantitate serum levels of human interleukin(IL)-6, IL-10, tissue growth factor-β1(TGF-β1), and IL-17 A.RESULTS We identified a decreased percentage of CD3+CD69+ cells in PHA-stimulated samples from SSc patients in comparison with healthy controls(13.35% ± 2.90% vs 37.03% ± 2.33%, P < 0.001). However, we did not establish a correlation between the down-regulated CD3+CD69+ cells and the clinical subset, nor regarding the stage of the disease. The activated CD4+CD25+ peripheral lymphocytes were represented in decreased percentage in patients when compared to controls(6.30% ± 0.68% vs 9.36% ± 1.08%, P = 0.016). Regarding the forms of the disease, dc SSc patients demonstrated lower frequency of CD4+CD25+ T cells against healthy subjects(5.95% ± 0.89% vs 9.36% ± 1.08%, P = 0.025). With regard to Th17 cells, our patients demonstrated increased percentage in comparison with controls(18.13% ± 1.55% vs 13.73% ± 1.21%, P = 0.031). We detected up-regulated Th17 cells within the lc SSc subset against controls(20.46% ± 2.41% vs 13.73% ± 1.21%, P = 0.025), nevertheless no difference was found between dc SSc and lc SSc patients. Flow cytometric analysis revealed an increased percentage of CD4+CD25-Foxp3+ in dc SSc patients compared to controls(10.94% ± 1.65% 展开更多
本研究旨在探讨免疫性血小板减少性紫癜(ITP)患者中T辅助细胞(helper T cell,Th)细胞免疫状态以及其与治疗反应的关系。应用实时荧光定量RT-PCR方法检测20例初发ITP患者(男性8例,女性12例,中位年龄41.0岁)接受糖皮质激素治疗[泼尼松1mg/...本研究旨在探讨免疫性血小板减少性紫癜(ITP)患者中T辅助细胞(helper T cell,Th)细胞免疫状态以及其与治疗反应的关系。应用实时荧光定量RT-PCR方法检测20例初发ITP患者(男性8例,女性12例,中位年龄41.0岁)接受糖皮质激素治疗[泼尼松1mg/(kg.d)]前后以及20例正常对照者外周血单个核细胞中Th细胞相关基因(T-bet、IFN-γ、GATA-3、TGF-β、Foxp3、IL-2、IL-4)表达水平的变化。结果表明:治疗前ITP患者外周血单个核细胞中T-bet、IFN-γ、IL-2表达较正常对照明显升高,差异有显著统计学意义(p<0.01),治疗后患者T-bet、IFN-γ、IL-2表达较治疗前降低(p<0.05);治疗前Foxp3表达较正常无明显变化,治疗后Foxp3表达较治疗前升高(p<0.05)。治疗前患者TGF-β的表达与正常对照相比无明显差别,治疗后老年患者与年轻患者中呈现不同的变化模式,年龄<60岁患者治疗后TGF-β表达水平较治疗前降低(p<0.05),而年龄≥60岁患者TGF-β较治疗前升高。结论:ITP患者存在Th细胞亚群失衡,常规糖皮质激素治疗仍是针对初治ITP患者的有效治疗手段,其作用机制可能与改善Th细胞亚群失衡有关。展开更多
文摘Naive CD4 T cells can differentiate into at least two different types ofT helpers, Thl and Th2 cells. Th2 cells, capable of producing IL-4, IL-5 and IL-13, are involved in humoral immunity against extracellular pathogens and in the induction of asthma and other allergic diseases. In this review, we summarize recent reports regarding the transcription factors involved in Th2 differentiation and cell expansion, including StatS, Gfi- 1 and GATA-3. Stats activation is necessary and sufficient for IL-2-mediated function in Th2 differentiation. Enhanced Stats signaling induces Th2 differentiation independent of IL-4 signaling; although it does not up-regulate GATA-3 expression, it does require the presence of GATA-3 for its action. Gfi-1, induced by IL-4, promotes the expansion of GATA-3-expressing cells. Analysis of conditional Gata3 knockout mice confirmed the critical role of GATA-3 in Th2 cell differentiation （both IL-4 dependent and IL-4 independent） and in Th2 cell proliferation and also showed the importance of basal GATA-3 expression in inhibiting Thl differentiation.
文摘Upon antigen stimulation, naive T helper cells differentiate into distinct lineages to attain specialized properties and effector functions. TH17 cells, a recently identified lineage of CD4＋ effector T cells, play a key role in the immune defense against fungi and extracellular bacteria, but also contribute to the pathogenesis of many autoimmune conditions. The differentiation of TH 17 cells is orchestrated by an intricate network of signaling pathways and transcriptional regulators in T cells. While the involvement of T cell-intrinsic pathways has been described extensively, we are just beginning to appreciate how TH17 cell development is shaped by extrinsic pathways, espec- ially the innate immune signals. Dendritic cells （DCs）, the most important cell type to bridge innate and adaptive immunity, drive TH17 cell differentiation by providing antigenic, costimulatory and cytokine signals. This is mediated by the recognition of innate and inflam- matory signals by DCs via pattern recognition receptors, cytokine receptors and other immunomodulatory receptors that in turn activate the intracellular signaling network. In particular, p38a MAP kinase has emerged as a critical pathway to program DC-dependent TH17 cell differentiation by integrating multiple instructive signals in DCs. Here, we summarize the current knowledge on the mechanisms by which DC-derived innate immune signals drive TH17 cell differentiation.
基金This study was supported by research grants from the National Natural Science Foundation of China(NO.81471475).
文摘The programmed cell death-1(PD-1)/PD-ligand 1(PD-L1)pathway is critical for normal pregnancy by promoting regulatory T(Treg)cell development and inhibiting the Th17 response.However,the relationship between the PD-1/PD-L1 pathway and the Treg/Th17 imbalance in pre-eclampsia(PE)is an enigma.In this study,decreased PD-1 and PD-L1 expression and a Treg/Th17 imbalance were observed at the maternal-fetal interface in PE.The regulatory effects of the PD-1/PD-L1 pathway on the Treg and Th17 cell quantities were determined in vitro by targeting T-cell proliferation,differentiation and transdifferentiation.First,decreased PD-1 expression might contribute to a higher Th17 cell frequency by promoting proliferation in PE.Second,the percentages of Treg but not Th17 cells differentiated from peripheral naive CD4+T cells were increased by PD-L1 Fc administration.This effect was accompanied by decreased PI3K/AKT/m-TOR and increased PTEN mRNA expression and was completely reversed by PD-1 blockade.Finally,the percentage of IL-17-producing Treg cells increased and was positively associated with the Th17 cell frequency in PE.Increased RORγt and IL-17 but not Foxp3 and IL-10 mRNA expression by Treg cells was observed with PD-1 blockade.Similar findings occurred when Treg cells were exposed to IL-6/IL-23/IL-1βand were reversed by PD-L1 Fc.Taken together,our findings indicate that the PD-1/PD-L1 pathway contributes to the Treg/Th17 imbalance via‘one-two punch’approaches:(i)promoting Th17 cell proliferation,(ii)inhibiting Treg cell differentiation and(iii)enhancing Treg cell plasticity into Th17 cells in PE.The therapeutic value of PD-L1 Fc for PE treatment will be explored in the future.
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AIM To investigate T-cell activation, the percentage of peripheral T regulatory cells(Tregs), Th17 cells and the circulating cytokine profile in systemic sclerosis(SSc).METHODS We enrolled a total of 24 SSc patients and 16 healthy controls in the study and divided the patients as having diffuse cutaneous SSc(dc SSc, n = 13) or limited cutaneous SSc(lc SSc, n = 11). We performed a further subdivision of the patients regarding the stage of the disease-early, intermediate or late. Peripheral venous blood samples were collected from all subjects. We performed flow cytometric analysis of the activationcapacity of T-lymphocytes upon stimulation with PHA-M and of the percentage of peripheral Tregs and Th17 cells in both patients and healthy controls. We used ELISA to quantitate serum levels of human interleukin(IL)-6, IL-10, tissue growth factor-β1(TGF-β1), and IL-17 A.RESULTS We identified a decreased percentage of CD3+CD69+ cells in PHA-stimulated samples from SSc patients in comparison with healthy controls(13.35% ± 2.90% vs 37.03% ± 2.33%, P < 0.001). However, we did not establish a correlation between the down-regulated CD3+CD69+ cells and the clinical subset, nor regarding the stage of the disease. The activated CD4+CD25+ peripheral lymphocytes were represented in decreased percentage in patients when compared to controls(6.30% ± 0.68% vs 9.36% ± 1.08%, P = 0.016). Regarding the forms of the disease, dc SSc patients demonstrated lower frequency of CD4+CD25+ T cells against healthy subjects(5.95% ± 0.89% vs 9.36% ± 1.08%, P = 0.025). With regard to Th17 cells, our patients demonstrated increased percentage in comparison with controls(18.13% ± 1.55% vs 13.73% ± 1.21%, P = 0.031). We detected up-regulated Th17 cells within the lc SSc subset against controls(20.46% ± 2.41% vs 13.73% ± 1.21%, P = 0.025), nevertheless no difference was found between dc SSc and lc SSc patients. Flow cytometric analysis revealed an increased percentage of CD4+CD25-Foxp3+ in dc SSc patients compared to controls(10.94% ± 1.65%
文摘本研究旨在探讨免疫性血小板减少性紫癜(ITP)患者中T辅助细胞(helper T cell,Th)细胞免疫状态以及其与治疗反应的关系。应用实时荧光定量RT-PCR方法检测20例初发ITP患者(男性8例,女性12例,中位年龄41.0岁)接受糖皮质激素治疗[泼尼松1mg/(kg.d)]前后以及20例正常对照者外周血单个核细胞中Th细胞相关基因(T-bet、IFN-γ、GATA-3、TGF-β、Foxp3、IL-2、IL-4)表达水平的变化。结果表明:治疗前ITP患者外周血单个核细胞中T-bet、IFN-γ、IL-2表达较正常对照明显升高,差异有显著统计学意义(p<0.01),治疗后患者T-bet、IFN-γ、IL-2表达较治疗前降低(p<0.05);治疗前Foxp3表达较正常无明显变化,治疗后Foxp3表达较治疗前升高(p<0.05)。治疗前患者TGF-β的表达与正常对照相比无明显差别,治疗后老年患者与年轻患者中呈现不同的变化模式,年龄<60岁患者治疗后TGF-β表达水平较治疗前降低(p<0.05),而年龄≥60岁患者TGF-β较治疗前升高。结论:ITP患者存在Th细胞亚群失衡,常规糖皮质激素治疗仍是针对初治ITP患者的有效治疗手段,其作用机制可能与改善Th细胞亚群失衡有关。
