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Inflammation-induced CD69^+ Kupffer cell feedback inhibits T cell proliferation via membrane-bound TGF-β1

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Science China(Life Sciences) 2016年第12期59卷 1259-1269页

作者： Xiang Zhang Zhengping Jiang Yan Gu Yanfang Liu Xuetao Cao Yanmei Han National Key Laboratory of medical immunology & institute of immunology Second Military Medical University National Key Laboratory of medical Molecular Biology & Department of immunology Institute of Basic Medical SciencesChinese Academy of Medical Sciences

Kupffer cells,tissue-resident macrophage lineage cell,are enriched in vertebrate liver.The mouse F4/80^+ Kupffer cells have been subclassified into two subpopulations according to their phenotype and function:CD68^+ subpopulation with potent reactive oxygen species(ROS) production and phagocytic capacities,and CD11b^+ subpopulation with a potent capacity to produce T helper 1 cytokines.In addition,CD11b^+ Kupffer cells/macrophages may be migrated from the bone marrow or spleen,especially in inflammatory conditions of the liver.For analyzing diverse Kupffer cell subsets,we infected mice with Listeria monocytogenes and analyzed the phenotype variations of hepatic Kupffer cells.During L.monocytogenes infection,hepatic CD69^+ Kupffer cells were significantly induced and expanded,and CD69^+ Kupffer cells expressed higher level of CD11 b,and particularly high level of membrane-bound TGF-β1(mTGF-β1) but lower level of F4/80.We also found that clodronate liposome administration did not eliminate hepatic CD69^+ Kupffer cell subset.We consider the hepatic CD69^+ Kupffer cell population corresponds to CD11b^+Kupffer cells,the bone marrow-derived population.Hepatic CD69^+ Kupffer cells suppressed Ag-nonspecific and OVA-specific CD4 T cell proliferation through mTGF-β1 both in vitro and in vivo,meanwhile,they did not interfere with activation of CD4 T cells.Thus,we have identified a new subset of inflammation-induced CD69^+ Kupffer cells which can feedback inhibit CD4 T cell response via cell surface TGF-β1 at the late stage of immune response against infection.CD69^+ Kupffer cells may contribute to protect host from pathological injure by preventing overactivation of immune response.

关键词： Kupffer 房间有免疫力的规定 CD69 TGF-1 Listeria monocytogenes

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Methyltransferase Dot1l preferentially promotes innate IL-6 and IFN-β production by mediating H3K79me2/3 methylation in macrophages

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Cellular & Molecular immunology 2020年第1期17卷 76-84页

作者： Xiang Chen Xingguang Liu Yunkai Zhang Wanwan Huai Qingqing Zhou Sheng Xu Xi Chen Nan Li Xuetao Cao National Key Laboratory of medical immunology&institute of immunology Second Military Medical UniversityShanghai 200433China institute of immunology Zhejiang University School of MedicineHangzhou 310058China Department of immunology&Center for Immunotherapy Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100005China

Epigenetic modification,including histone modification,precisely controls target gene expression.The posttranscriptional regulation of the innate signaling-triggered production of inflammatory cytokines and type I interferons has been fully elucidated,whereas the roles of histone modification alteration and epigenetic modifiers in regulating inflammatory responses need to be further explored.Di/tri-methylation modifications of histone 3 lysine 79(H3K79me2/3)have been shown to be associated with gene transcriptional activation.Disruptor of telomeric silencing-1-like(Dot1l)is the only known exclusive H3K79 methyltransferase and regulates the proliferation and differentiation of tumor cells.However,the roles of Dot1l and Dot1l-mediated H3K79 methylation in innate immunity and inflammatory responses remain unclear.Here,we found that H3K79me2/3 modification levels at the Il6 and Ifnb1 promoters,as well as H3K79me2 modification at the Tnfαpromoter,were increased in macrophages activated by Toll-like receptor(TLR)ligands or virus infection.The innate signals upregulated Dot1l expression in macrophages and THP1 cells.Dot1l silencing or a Dot1l inhibitor preferentially suppressed the production of IL-6 and interferon(IFN)-βbut not of TNFαin macrophages and THP1 cells triggered by TLR ligands or virus infection.Dot1l was recruited to the proximal promoter of the Il6 and Ifnb1 but not Tnfαgene and then mediated H3K79me2/3 modification at the Il6 and Ifnb1 promoters,consequently facilitating the transcription and expression of Il6 and Ifnb1.Thus,Dot1l-mediated selective H3K79me2/3 modifications at the Il6 and Ifnb1 promoters are required for the full activation of innate immune responses.This finding adds new insights into the epigenetic regulation of inflammatory responses and pathogenesis of autoimmune diseases.

关键词： H3K79me2/3 Dot1l epigenetic regulation IL-6 IFN-β macrophages inflammation

Intracellular HSP70L1 inhibits human dendritic cell maturation by promoting suppressive H3K27me3 and H2AK119Ub1 histone modifications

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Cellular & Molecular immunology 2020年第1期17卷 85-94页

作者： Lin Yi Zhiqing Li Tianju Hu Juan Liu Nan Li Xuetao Cao Shuxun Liu National Key Laboratory of medical immunology&institute of immunology Second Military Medical University200433ShanghaiChina Department of immunology&Center for Immunotherapy Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical Sciences100005 BeijingChina

Epigenetic regulation has been attracting increasing attention due to its role in cell differentiation and behaviors.However,the epigenetic mechanisms that regulate human dendritic cell(DC)differentiation and development remain poorly understood.Our previous studies show that extracellular heat shock protein 70-like protein(HSP70L1)is a potent adjuvant of Th1 responses via stimulating DCs when released from cells;however,the role of intracellular HSP70L1 in DC differentiation and maturation remains unknown.Herein,we demonstrate that intracellular HSP70L1 inhibits human DC maturation by suppressing MHC and costimulatory molecule expression,in contrast to the adjuvant activity of extracellular HSP70L1.The stability of intracellular HSP70L1 is dependent on DNAJC2,a known epigenetic regulator.Mechanistically,intracellular HSP70L1 inhibits the recruitment of Ash1l to and maintains the repressive H3K27me3 and H2AK119Ub1 modifications on the promoter regions of costimulatory,MHC and STAT3 genes.Thus,intracellular HSP70L1 is an inhibitor of human DC maturation.Our results provide new insights into the epigenetic regulation of cell development by intracellular HSP70L1.

关键词： HSP70L1 DNAJC2 Monocyte-derived dendritic cell Histone modification H3K27me3 H2AK119Ub1 H3K4me3

Immunomodulatory effects of astragalus polysaccharide on Human peripheral blood mononuclear cells co-cultured with cervical cancer cell lineImmunomodulatory effects of astragalus polysaccharide on Human peripheral blood mononuclear cells co-cultured with cervical cancer cell line

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Journal of Traditional Chinese Medicine 2021年第5期41卷 684-694页

作者： Elham Shokati Mohammad-Reza Shokri Kobra Entezami Samaneh Khorrami Mona Amani Morteza Motallebnezhad Elahe Safari immunology Research Center Institute of Immunology and Infectious DiseasesIran University of Medical SciencesTehran ***Iran Department of immunology Faculty of Medical SciencesIran University of Medical SciencesTehran ***Iran Department of immunology School of Public HealthTehran University of Medical SciencesTehran ***Iran

OBJECTIVE:To investigate immunomodulatory effects of Astragalus polysaccharides(APS)on the co-culture of peripheral blood mononuclear cells(PBMCs)with He La cervical cancer cell line.METHODS:To assess the proliferation of PBMCs,carboxyfluorescein succinimidyl ester(CFSE)-labeled PBMCs were co-cultured with He La cells and treated with different concentrations of APS.Supernatants of cell culture were collected for cytokines assay via enzyme-linked immunosorbent assay(ELISA).The impact of APS on the proliferation of PBMCs,induction of regulatory T cells(Tregs),and myeloid-derived suppressor cells(MDSCs)was carried out by flow cytometry.RESULTS:It was observed that APS could increase the proliferation of PBMCs co-cultured with He La cells(P0.05).Furthermore,ELISA results demonstrated that APS could decrease IL-10 and TGF-βconcentration(P<0.05).CONCLUSION:The above-mentioned characteristics showed that APS might be able to modulate immune responses and improve anti-tumor effects through increasing the proliferation of PBMCs and decreasing inhibitory cytokines secretion as critical mediators of immune suppression in the tumor microenvironment.

关键词： Astragalus polysaccharides uterine cervical neoplasms HeLa cells coculture techniques cytokines T-lymphocytes,regulatory

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The methyltransferase PRMT6 attenuates antiviral innate immunity by blocking TBK1–IRF3 signaling

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Cellular & Molecular immunology 2019年第10期16卷 800-809页

作者： Hua Zhang Chaofeng Han Tianliang Li Nan Li Xuetao Cao National Key Laboratory of medical immunology&institute of immunology Second Military Medical UniversityShanghai 200433China Department of immunology&Center for Immunotherapy Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing 100005China

Protein arginine methyltransferases(PRMTs)play diverse biological roles and are specifically involved in immune cell development and inflammation.However,their role in antiviral innate immunity has not been elucidated.Viral infection triggers the TBK1–IRF3 signaling pathway to stimulate the production of type-I interferon,which mediates antiviral immunity.We performed a functional screen of the nine mammalian PRMTs for regulators of IFN-βexpression and found that PRMT6 inhibits the antiviral innate immune response.Viral infection also upregulated PRMT6 protein levels.We generated PRMT6-deficient mice and found that they exhibited enhanced antiviral innate immunity.PRMT6 deficiency promoted the TBK1–IRF3 interaction and subsequently enhanced IRF3 activation and type-I interferon production.Mechanistically,viral infection enhanced the binding of PRMT6 to IRF3 and inhibited the interaction between IRF3 and TBK1;this mechanism was independent of PRMT6 methyltransferase activity.Thus,PRMT6 inhibits antiviral innate immunity by sequestering IRF3,thereby blocking TBK1-IRF3 signaling.Our work demonstrates a methyltransferase-independent role for PRMTs.It also identifies a negative regulator of the antiviral immune response,which may protect the host from the damaging effects of an overactive immune system and/or be exploited by viruses to escape immune detection.

关键词： PRMT6 TBK1 IRF3 IFN antiviral innate immunity

Metabolic control of T-cell immunity via epigenetic mechanisms

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Cellular & Molecular immunology 2018年第3期15卷 203-205页

作者： Xiaomin Zhang Juan Liu Xuetao Cao National Key Laboratory of medical immunology&institute of immunology Second Military Medical UniversityShanghai200433China Department of immunology and Center for Immunotherapy Institute of Basic Medical SciencesChinese Academy of Medical SciencesBeijing100005China

Metabolism has been increasingly considered to play an important role in inflammation and immunity via modulating cellular signaling and transcriptional networks.1 Dysregulation of metabolic enzymes or mediators is increasingly linked to clinical diseases,such as type I diabetes,gliomas and breast cancer.2,3 Numerous metabolic sensors,such as AMP-mediated protein kinase,mammalian target of rapamycin complex1 and hypoxia-induced factor 1α(HIF-1α),have been shown to regulate immunological responses,such as T-cell activation and macrophage polarization,via modulating the property and activity of signaling pathways.4,5 Moreover,emerging evidence suggests that intermediates from multiple metabolic pathways are important in orchestrating transcriptional and epigenetic programs.This interaction between metabolic and epigenetic pathways is crucial for coordinating cellular immunological events in response to extracellular stimuli,such as infection,injury and stress,leading to varied biological and pathological outcomes.

关键词： immunity epigenetic inflammation

MicroRNA in vivo precipitation identifies miR-151-3p as a computational unpredictable miRNA to target Stat3 and inhibits innate IL-6 production

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Cellular & Molecular immunology 2018年第2期15卷 99-110页

作者： Xiang Liu Xiaoping Su Sheng Xu Huamin Wang Dan Han Jiangxue Li Mingyan Huang Xuetao Cao National Key Laboratory of medical immunology&institute of immunology Second Military Medical UniversityShanghai200433China Department of immunology&Center for Immunotherapy Institute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical SciencesBeijing100005China institute of immunology Zhejiang University School of MedicineHangzhou310058China

MicroRNAs(miRNAs)function as important regulators in the immune response and inflammation.Several approaches have been reported to computationally predict miRNAs and their potential targets.However,there are still many miRNA–target interactions that are unpredictable by using the current computational algorithms.We established a miRNA in vivo precipitation method(miRIP)to identify unpredictable miRNAs with definite targets in these cells.Because Stat3 is a well-known transcription factor involved in innate immunity and inflammation,we utilized the miRIP method to identify miRNAs that bind Stat3 mRNA in macrophages.Among the captured miRNAs,miR-151-3p was confirmed to interact with Stat3 mRNA 3′-UTR and downregulate the Stat3 protein levels.LPS stimulation decreased miR-151-3p expression,thereby increasing IL-6 production.Therefore,we found that miR-151-3p inhibited LPS-induced IL-6 production by targeting Stat3.These data further confirmed miRIP as an efficient method to identify unpredictable miRNAs and explore miRNAs-mediated regulation in innate immunity and inflammation.

关键词： innate immunity IL-6 macrophage miR-151-3p Stat3

Selection and characterization of the novel anti-human PD-1 FV78 antibody from a targeted epitope mammalian cell-displayed antibody library

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Cellular & Molecular immunology 2018年第2期15卷 146-157页

作者： Longlong Luo Shi Wang Xiaoling Lang Tingting Zhou Jing Geng Xinying Li Chunxia Qiao Jiannan Feng Beifen Shen Ming Lv Yan Li Laboratory of immunology Institute of Basic Medical SciencesBeijing100850China Laboratory of Cellular and Molecular immunology Institute of ImmunologyHenan UniversityKaifeng475001China

Currently,display-based methods are well established and widely used in antibody engineering for affinity maturation and structural stability improvement.We obtained a novel anti-human programmed death 1(PD-1)antibody using computer-aided design and a mammalian cell display technology platform.We used computer-aided modeling and distance geometry methods to predict and assign the key residues that contributed to the binding of human PD-L1 to PD-1.Then,we analyzed the sequence of nivolumab(an anti-human PD-1 antibody,referred to as MIL75 in the article)to determine the template for antibody design and library construction.We identified a series of potential substitutions on the obtained template and constructed a virtual epitope-targeted antibody library based on the physicochemical properties and each possible location of the assigned key residues.The virtual antibody libraries were displayed on the surface of mammalian cells as the antigen-binding fragments of full-length immunoglobulin G.Then,we used flow cytometry and sequencing approaches to sort and screen the candidates.Finally,we obtained a novel anti-human PD-1 antibody named FV78.FV78 competitively recognized the PD-1 epitopes that interacted with MIL75 and possessed an affinity comparable to MIL75.Our results implied that FV78 possessed equivalent bioactivity in vitro and in vivo compared with MIL75,which highlighted the probability and prospect of FV78 becoming a new potential antibody therapy.

关键词： antibody computer-guided modeling distance geometry human PD-1 mammalian cell-displayed antibody library

cGAS-STING pathway in senescence-related inflammation

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National Science Review 2018年第3期5卷 308-310页

作者： Kun Chen Juan Liu Xuetao Cao National Key Laboratory of medical Molecular Biology Department of Immunology & Center for Immunotherapy Institute of Basic Medical Sciences Peking Union Medical College Chinese Academy of Medical Sciences National Key Laboratory of medical immunology & institute of immunology Second Military Medical University

Cellular senescence marked with persistent cell cycle arrest plays critical roles in orchestrating tissue remodeling and immune surveillance in response to multiple developmental and physiological stimuli.However,chronic or persistent cellular senescence can promote aberrant inflammatory responses,therefore is linked with variable pathogeneses such as fibrosis,cancer,autoimmune diseases,

关键词： GAS cGAS-STING pathway in senescence-related inflammation