Interferon-gamma （IFN-γ） is a major proinflammatory effector and regulatory cytokine produced by activated T cells and NK cells. IFN-γ has been shown to play pivotal roles in fundamental immunological processes su...Interferon-gamma （IFN-γ） is a major proinflammatory effector and regulatory cytokine produced by activated T cells and NK cells. IFN-γ has been shown to play pivotal roles in fundamental immunological processes such as inflammatory reactions, cell-mediated immunity and autoimmunity. A variety of human disorders have now been linked to irregular IFN-γ expression. In order to achieve proper IFN-γ-mediated immunological effects, IFN-γ expression in T cells is subject to both positive and negative regulation. In this study, we report for the first time the negative regulation of IFN-γ expression by Prospero-related Homeobox （Proxl）. In Jurkat T cells and primary human CD4＋ T cells, Proxl expression decreases quickly upon T cell activation, concurrent with a dramatic increase in IFN-γ expression. Reporter analysis and chromatin immunoprecipitation （CHIP） revealed that Proxl associates with and inhibits the transcription activity of IFN-γ promoter in activated Jurkat T cells. Co-immunoprecipitation and GST pull-down assay demonstrated a direct binding between Proxl and the nuclear receptor peroxisome proliferator-activated receptor gamma （PPARγ）, which is also an IFN-γ repressor in T cells. By introducing deletions and mutations into Proxl, we show that the repression of IFN-γ promoter by Proxl is largely dependent upon the physical interaction between Proxl and PPARγ. Furthermore, PPARγ antagonist treatment removes Proxl from IFN-γ promoter and attenuates repression of IFN-γ expression by Proxl. These findings establish Proxl as a new negative regulator of IFN-γ expression in T cells and will aid in the understanding of IFN-γ transcription regulation mechanisms.展开更多
Chronic schistosome infection results in the suppression of host immune responses, allowing long-term schistosome survival and restricting pathology.Current theories suggest that Treg play an important role in this re...Chronic schistosome infection results in the suppression of host immune responses, allowing long-term schistosome survival and restricting pathology.Current theories suggest that Treg play an important role in this regulation.However, the mechanism of Treg induction during schistosome infection is still unknown.The aim of this study was to determine the mechanism behind the induction of CD4(+)CD25(+) T cells by Schistosoma japonicum HSP60(SjHSP60)-derived peptide SJMHE1 as well as to elucidate the cellular and molecular basis for the induction of CD4(+)CD25(+) T cells during S.japonicum infection.Mice immunized with SJMHE1 or spleen and LN cells from naive mice pretreated.with SJMHE1 in vitro all displayed an increase in CD4(+)CD25(+) T-cell populations.Release of IL-10 and TGF-beta by SJMHE1 stimulation may contribute to suppression.Adoptively transferred SJMHE1induced CD4(+)CD25(+) T cells inhibited delayed-type hypersensitivity in BALB / c mice.Additionally, SJMHE1-treated APC were tolerogenic and induced CD4(+) cells to differentiate into suppressive CD4(+)CD25(+) Treg.Furthermore, our data support a role for TLR2 in SJMHE1-mediated CD4(+)CD25(+) Treg induction.These findings provide the basis for a more complete understanding of the S.japonicum-host interactions that contribute to host homeostatic mechanisms, preventing an excessive immune response.展开更多
Inhibitory checkpoint molecules include programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),cytotoxic T lymphocyte antigen-4(CTLA-4),human endogenous retrovirus-H Long terminal repeat-associating 2(HHL...Inhibitory checkpoint molecules include programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),cytotoxic T lymphocyte antigen-4(CTLA-4),human endogenous retrovirus-H Long terminal repeat-associating 2(HHLA2),B7 homolog 4 protein(B7-H4),T cell membrane protein-3(TIM-3)and Lymphocyte-activation gene 3(LAG-3),which are up-regulated during tumorigenesis.These pathways are essential to down-regulate the immune system by blocking the activation of T cells.In recent years,immune checkpoint blockers(ICBs)against PD-1,PD-L1,CTLA-4 or TIM-3 has made remarkable progress in the clinical application,revolutionizing the treatment of malignant tumors and improving patients’overall survival.However,the efficacy of ICBs in some patients does not seem to be good enough,and more immune-related adverse events(irAEs)will inevitably occur.Therefore,biomarkers research provides practical guidance for clinicians to identify patients who are most likely to benefit from or exhibit resistance to particular types of immune checkpoint therapy.There are two points in general.On the one hand,given the spatial and temporal differential expression of immune checkpoint molecules during immunosuppression process,it is essential to understand their mechanisms to design the most effective individualized therapy.On the other hand,due to the lack of potent immune checkpoints,it is necessary to combine them with novel biomarkers(such as exosomes and ctDNA)and other anticancer modalities(such as chemotherapy and radiotherapy).展开更多
Germinal centers(GCs)are essential for the establishment of long-lasting antibody responses.GC B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into funct...Germinal centers(GCs)are essential for the establishment of long-lasting antibody responses.GC B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into functional changes in the cell proteome.However,the critical proteins driving these key mechanisms are still unknown.Here,we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC responses.TIA1-and TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection,expansion and differentiation into B-cell clones producing high-affinity antibodies.Mechanistically,TIA1 and TIAL1 control the transcriptional identity of dark-and light-zone GC B cells and enable timely expression of the prosurvival molecule MCL1.Thus,we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.展开更多
全球有超过7 000万名丙型肝炎病毒(Hepatitis C virus,HCV)慢性感染患者,给社会带来严重的公共卫生安全问题。直接抗病毒药物(Direct antiviral drugs,DAA)能够有效地治愈慢性丙型肝炎病毒感染,但治愈后患者仍存在再感染的可能,预防性疫...全球有超过7 000万名丙型肝炎病毒(Hepatitis C virus,HCV)慢性感染患者,给社会带来严重的公共卫生安全问题。直接抗病毒药物(Direct antiviral drugs,DAA)能够有效地治愈慢性丙型肝炎病毒感染,但治愈后患者仍存在再感染的可能,预防性疫苗(Prophylactic vaccine)是彻底切断HCV传播的最有效途径。目前HCV预防性疫苗的研发已取得一定进展,能够诱导极少数受试者产生广谱中和抗体(Broadly neutralizing antibodies),如何在绝大多数个体中诱导保护性广谱中和抗体则是当前HCV预防性疫苗研究所面临的最大挑战。本文总结了当前疫苗免疫学的研究进展:包括抗原特异的B细胞前体(Precursor B cell)、滤泡辅助性T细胞(Follicular T helper cell,Tfh)、滤泡调节性T细胞(Follicular T regulatory cell,Tfr)、抗体重链基因1-69(VH1-69)编码抗体成熟特点;基于胚系靶向(Germline-targeting)的免疫原设计与序贯免疫策略(Sequential immunization)等,期望能为HCV疫苗研究提供新的思路。展开更多
文摘Interferon-gamma （IFN-γ） is a major proinflammatory effector and regulatory cytokine produced by activated T cells and NK cells. IFN-γ has been shown to play pivotal roles in fundamental immunological processes such as inflammatory reactions, cell-mediated immunity and autoimmunity. A variety of human disorders have now been linked to irregular IFN-γ expression. In order to achieve proper IFN-γ-mediated immunological effects, IFN-γ expression in T cells is subject to both positive and negative regulation. In this study, we report for the first time the negative regulation of IFN-γ expression by Prospero-related Homeobox （Proxl）. In Jurkat T cells and primary human CD4＋ T cells, Proxl expression decreases quickly upon T cell activation, concurrent with a dramatic increase in IFN-γ expression. Reporter analysis and chromatin immunoprecipitation （CHIP） revealed that Proxl associates with and inhibits the transcription activity of IFN-γ promoter in activated Jurkat T cells. Co-immunoprecipitation and GST pull-down assay demonstrated a direct binding between Proxl and the nuclear receptor peroxisome proliferator-activated receptor gamma （PPARγ）, which is also an IFN-γ repressor in T cells. By introducing deletions and mutations into Proxl, we show that the repression of IFN-γ promoter by Proxl is largely dependent upon the physical interaction between Proxl and PPARγ. Furthermore, PPARγ antagonist treatment removes Proxl from IFN-γ promoter and attenuates repression of IFN-γ expression by Proxl. These findings establish Proxl as a new negative regulator of IFN-γ expression in T cells and will aid in the understanding of IFN-γ transcription regulation mechanisms.
文摘Chronic schistosome infection results in the suppression of host immune responses, allowing long-term schistosome survival and restricting pathology.Current theories suggest that Treg play an important role in this regulation.However, the mechanism of Treg induction during schistosome infection is still unknown.The aim of this study was to determine the mechanism behind the induction of CD4(+)CD25(+) T cells by Schistosoma japonicum HSP60(SjHSP60)-derived peptide SJMHE1 as well as to elucidate the cellular and molecular basis for the induction of CD4(+)CD25(+) T cells during S.japonicum infection.Mice immunized with SJMHE1 or spleen and LN cells from naive mice pretreated.with SJMHE1 in vitro all displayed an increase in CD4(+)CD25(+) T-cell populations.Release of IL-10 and TGF-beta by SJMHE1 stimulation may contribute to suppression.Adoptively transferred SJMHE1induced CD4(+)CD25(+) T cells inhibited delayed-type hypersensitivity in BALB / c mice.Additionally, SJMHE1-treated APC were tolerogenic and induced CD4(+) cells to differentiate into suppressive CD4(+)CD25(+) Treg.Furthermore, our data support a role for TLR2 in SJMHE1-mediated CD4(+)CD25(+) Treg induction.These findings provide the basis for a more complete understanding of the S.japonicum-host interactions that contribute to host homeostatic mechanisms, preventing an excessive immune response.
基金the National Natural Science Foundation of China(81872200,31900558)the Natural Science Foundation of Hubei Province(2018CFB510)+1 种基金the Zhongnan Hospital of Wuhan University Science,Technology and Innovation Seed Fund(CXPY2017029)the Fundamental Research Funds for the Central Universities(2042018kf0091).
文摘Inhibitory checkpoint molecules include programmed cell death-1(PD-1),programmed cell death ligand-1(PD-L1),cytotoxic T lymphocyte antigen-4(CTLA-4),human endogenous retrovirus-H Long terminal repeat-associating 2(HHLA2),B7 homolog 4 protein(B7-H4),T cell membrane protein-3(TIM-3)and Lymphocyte-activation gene 3(LAG-3),which are up-regulated during tumorigenesis.These pathways are essential to down-regulate the immune system by blocking the activation of T cells.In recent years,immune checkpoint blockers(ICBs)against PD-1,PD-L1,CTLA-4 or TIM-3 has made remarkable progress in the clinical application,revolutionizing the treatment of malignant tumors and improving patients’overall survival.However,the efficacy of ICBs in some patients does not seem to be good enough,and more immune-related adverse events(irAEs)will inevitably occur.Therefore,biomarkers research provides practical guidance for clinicians to identify patients who are most likely to benefit from or exhibit resistance to particular types of immune checkpoint therapy.There are two points in general.On the one hand,given the spatial and temporal differential expression of immune checkpoint molecules during immunosuppression process,it is essential to understand their mechanisms to design the most effective individualized therapy.On the other hand,due to the lack of potent immune checkpoints,it is necessary to combine them with novel biomarkers(such as exosomes and ctDNA)and other anticancer modalities(such as chemotherapy and radiotherapy).
基金We thank all personnel from the Toulouse animal facility CREFRE and from the flow cytometry,imaging,transcriptomics and bioinformatics technical platforms of INFINITy.M.D.D-M.is supported by ATIP-Avenir-Plan Cancer(C18003BS),ANR(ANR-20-CE15-0007)foundation ARSEP R19201BB,foundation ARC,La Ligue Contre Le Cancer and INSPIRE(Region Occitanie,Inserm and CHU Toulouse)M.T.is supported with a BBSRC core funding grant and a Wellcome Investigator award(200823/Z/16/Z).D.C.-S.is supported by Boehringer Ingelheim Fonds.
文摘Germinal centers(GCs)are essential for the establishment of long-lasting antibody responses.GC B cells rely on post-transcriptional RNA mechanisms to translate activation-associated transcriptional programs into functional changes in the cell proteome.However,the critical proteins driving these key mechanisms are still unknown.Here,we show that the RNA binding proteins TIA1 and TIAL1 are required for the generation of long-lasting GC responses.TIA1-and TIAL1-deficient GC B cells fail to undergo antigen-mediated positive selection,expansion and differentiation into B-cell clones producing high-affinity antibodies.Mechanistically,TIA1 and TIAL1 control the transcriptional identity of dark-and light-zone GC B cells and enable timely expression of the prosurvival molecule MCL1.Thus,we demonstrate here that TIA1 and TIAL1 are key players in the post-transcriptional program that selects high-affinity antigen-specific GC B cells.
文摘全球有超过7 000万名丙型肝炎病毒(Hepatitis C virus,HCV)慢性感染患者,给社会带来严重的公共卫生安全问题。直接抗病毒药物(Direct antiviral drugs,DAA)能够有效地治愈慢性丙型肝炎病毒感染,但治愈后患者仍存在再感染的可能,预防性疫苗(Prophylactic vaccine)是彻底切断HCV传播的最有效途径。目前HCV预防性疫苗的研发已取得一定进展,能够诱导极少数受试者产生广谱中和抗体(Broadly neutralizing antibodies),如何在绝大多数个体中诱导保护性广谱中和抗体则是当前HCV预防性疫苗研究所面临的最大挑战。本文总结了当前疫苗免疫学的研究进展:包括抗原特异的B细胞前体(Precursor B cell)、滤泡辅助性T细胞(Follicular T helper cell,Tfh)、滤泡调节性T细胞(Follicular T regulatory cell,Tfr)、抗体重链基因1-69(VH1-69)编码抗体成熟特点;基于胚系靶向(Germline-targeting)的免疫原设计与序贯免疫策略(Sequential immunization)等,期望能为HCV疫苗研究提供新的思路。
