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

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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HSP70L1-mediated intracellular priming of dendritic cell vaccination induces more potent CTL response against cancer

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Cellular & molecular immunology 2018年第2期15卷 135-145页

作者： Shuxun Liu Lin Yi Ma Ling Jinxia Jiang Lijun Song Juan Liu Xuetao Cao national key laboratory of medical immunology Institute of ImmunologySecond Military Medical UniversityShanghai200433China department of immunology National Key Laboratory of Medical Molecular BiologyChinese Academy of Medical SciencesBeijing100730China

Heat-shock protein(HSP)-based immunotherapy is established on its adjuvant effects when applied via an extracellular approach to pulse and activate dendritic cells(DCs).Our previous studies indicate that DCs pulsed with recombinant fusion proteins of antigenic fragment and HSP70-like protein 1(HSP70L1)are potent in stimulating antigen-specific Th1 responses.We herein evaluated the cytotoxic T cell(CTL)response by an intracellular approach of priming DCs with transfection of recombinant adenovirus-expressing the fusion gene of the 576–699 fragment of carcinoembryonic antigen(CEA)and HSP70L1.As compared with DCs pulsed with extracellular fusion protein,the DCs transfected with recombinant adenovirus expressing the fusion gene displayed equivalent mature phenotypes but less inflammatory appearance.However,the transfected DCs were superior to the pulsed DCs in inducing CEA-specific CTLs.Consistently,immunization of HLA-A2.1/H-2Kb transgene mice with the transfected DCs could induce more quantities of HLA-A2.1-restricted CEA-specific CTLs,protecting nude mice more significantly from human CEA-expressing colon tumor challenge when adoptively transferred.Mechanistic investigation indicated that intracellular expression of the fusion protein empowered the transfected DCs by activation of STAT1 possibly via inducing IFN-βand ERK pathways.Therefore,the more potent ability to induce anti-CEA CTL responses enables the DCs,which transfected with recombinant adenovirus expressing the fusion gene of antigenic CEA fragment and Th1 adjuvant,as an alternative promising approach for the immunotherapy of CEA-positive tumors.

关键词： CTL dendritic cell HSP70L1 immunotherapy

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GSDME with a moonlighting function in pancreatic ductal adenocarcinoma: a narrative review

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Journal of Pancreatology 2022年第4期5卷 83-104页

作者： Bo Huang Department of Immunology&National Key Laboratory of Medical Molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China department of Biochemistry&molecular biology Tongji Medical CollegeHuazhong University of Science&TechnologyWuhan 430030China

Pancreatic ductal adenocarcinoma(PDAC)originates in the exocrine pancreas and accounts for 95%of pancreatic cancers,with 5-year survival rates of approximately 10%.Multiple factors are involved in PDAC pathogenesis,including internal genetic alterations and external inflammation-related stimuli.Overflow of exocrine pancreatic enzymes caused by PDAC obstruction inevitably results in autolysis of surrounding normal cells and extracellular matrix,generating tissue damage-related inflammation;however,this process does not cause autolysis of PDAC cells.How tumor cells acquire resistance to pancreatic enzymatic digestion has been ignored for a long time.In this review,we discuss how PDAC cells mobilize gasdermin E,a pore-forming protein,to achieve resistance to autolysis by pancreatic digestive enzymes.

关键词： PDAC GSDME mucins pancreatic enzymes

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Advances in innate immune signaling:new activators and regulators

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national Science Review 2016年第2期3卷 160-162页

作者： Juan Liu Xuetao Cao 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

The innate immune system can detect the invading microbe components via three major pattern recognition receptorsToll-like receptors,RIG-I-like receptors and NOD-like receptors as well as a variety of cytoplasmic DNA or RNA sensors.These innate receptors induce a series of intracellular downstream signaling pathways,leading to the efficient innate immune responses to eliminate pathogens(Fig.1).Meanwhile,

关键词： Advances in innate immune signaling IKK DNA TLR

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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

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Macrophages’M1 or M2 by tumor microparticles:lysosome makes decision

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Cellular & molecular immunology 2022年第10期19卷 1196-1197页

作者： Ke Tang Jingwei Ma Bo Huang department of Biochemistry and molecular biology Tongji Medical CollegeHuazhong University of Science and Technology430030WuhanChina Cell Architecture Research Center Huazhong University of Science and Technology430030WuhanChina department of immunology Tongji Medical CollegeHuazhong University of Science and Technology430030WuhanChina Department of Immunology&National Key Laboratory of Medical Molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical Sciences(CAMS)&Peking Union Medical College100005BeijingChina

Cells deliver messages to their surroundings or distant cells by secreting signaling molecules or releasing extracellular microvesicles(EVs)[1,2].Two types of EVs have been identified:exosomes and microparticles(MPs),which are also termed microvesicles(MVs).Exosomes are endosome-derived EVs(30-100 nm)that deliver information about proteins,mRNAs,and microRNAs to recipient cells[3].MPs are plasma membrane-derived shedding vesicles with sizes ranging from 0.1 to 1μm[4].

关键词： releasing sizes deliver

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Highlights of the advances in basic immunology in 2011

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Cellular & molecular immunology 2012年第3期9卷 197-207页

作者： Juan Liu Shuxun Liu Xuetao Cao national key laboratory of medical immunology and Institute of immunology Second Military Medical UniversityShanghaiChina national key laboratory of medical molecular biology and department of immunology Chinese Academy of Medical SciencesBeijingChina

In this review, we summarize the major fundamental advances in immunological research reported in 2011. The highlights focus on the improved understanding of key questions in basic immunology, including the initiation and activation of innate responses as well as mechanisms for the development and function of various T-cell subsets. The research includes the identification of novel cytosolic RNA and DNA sensors as well as the identification of the novel regulators of the Toll-like receptor （TLR） and retinoic acid-inducible gene I （RIG-I）-Iike receptor （RLR） signaling pathway. Moreover, remarkable advances have been made in the developmental and functional properties of innate lymphoid cells （I LCs）. Helper T cells and regulatory T （Treg） cells play indispensable roles in orchestrating adaptive immunity. There have been exciting discoveries regarding the regulatory mechanisms of the development of distinct T-cell subsets, particularly Th17 cells and Treg cells. The emerging roles of microRNAs （miRNAs） in T cell immunity are discussed, as is the recent identification of a novel T-cell subset referred to as follicular regulatory T （TFR） cells.

关键词： ILC innate immunity Th17 cells TFR cells TLR

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Long noncoding RNAs in innate immunity

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Cellular & molecular immunology 2016年第2期13卷 138-147页

作者： Yuan Zhang Xuetao Cao national key laboratory of medical molecular biology & department of immunology Institute of Basic Medical Sciences Chinese Academy of MedicalSciences Beijing 100005 China

Long noncoding RNAs （IncRNAs） have been shown to play important roles in immune cell development and immune responses through different mechanisms, such as dosage compensation, imprinting, enhancer function, and transcriptional regulation. Although the functions of most IncRNAs are unclear, some IncRNAs have been found to control transcriptional or post-transcriptional regulation of the innate and adaptive immune responses via new methods of protein-protein interactions or pairing with DNA and RNA. Interestingly, increasing evidence has elucidated the importance of IncRNAs in the interaction between hosts and pathogens. In this review, an overview of the IncRNAs modes of action, as well as the important and diversified roles of IncRNAs in immunity, are provided, and an emerging paradigm of IncRNAs in regulating innate immune responses is highlighted.

关键词： host-pathogen interaction innate immunity long noncoding RNA

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Fine-tuning MAVS- and STING-mediated antiviral innate immunity

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national Science Review 2015年第3期2卷 262-264页

作者： Xingguang Liu Xuetao Cao 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 Sciences Chinese Academy of Medical Sciences

The pathogen-associated molecules or nucleic acids derived from the invading pathogens can initiate the production of type I interferons(IFNs)and IFN-inducible genes,resulting in the establishment of an efective antimicrobial environment.In case of viral infection,nucleic acids from viruses are detected by patern recognition receptors mainly including several endosomal members of

关键词： Fine-tuning MAVS and STING-mediated antiviral innate immunity IFN

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Alveolar macrophages:Achilles’heel of SARS-CoV-2 infection

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Signal Transduction and Targeted Therapy 2022年第8期7卷 2936-2944页

作者： Zhenfeng Wang Shunshun Li Bo Huang Department of Immunology&National Key Laboratory of Medical Molecular Biology Institute of Basic Medical SciencesChinese Academy of Medical Sciences(CAMS)&Peking Union Medical College100005 BeijingChina department of immunology Basic Medicine CollegeChina Medical University110122 ShenyangLiaoningChina department of Biochemistry&molecular biology Tongji Medical CollegeHuazhong University of Science&Technology430030 WuhanChina

The coronavirus disease 2019(COVID-19)pandemic has caused more than 6.3 million deaths to date.Despite great efforts to curb the spread of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),vaccines and neutralizing antibodies are in the gloom due to persistent viral mutations and antiviral compounds face challenges of specificity and safety.In addition,vaccines are unable to treat already-infected individuals,and antiviral drugs cannot be used prophylactically.Therefore,exploration of unconventional strategies to curb the current pandemic is highly urgent.Alveolar macrophages(AMs)residing on the surface of alveoli are the first immune cells that dispose of alveoli-invading viruses.Our findings demonstrate that M1 AMs have an acidic endosomal pH,thus favoring SARS-CoV-2 to leave endosomes and release into the cytosol where the virus initiates replication;in contrast,M2 AMs have an increased endosomal pH,which dampens the viral escape and facilitates delivery of the virus for lysosomal degradation.In this review,we propose that AMs are the Achilles’heel of SARS-CoV-2 infection and that modulation of the endosomal pH of AMs has the potential to eliminate invaded SARS-CoV-2;the same strategy might also be suitable for other lethal respiratory viruses.

关键词： eliminate spite neutral

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