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CTLA4 protects against maladaptive cytotoxicity during the differentiation of effector and follicular CD4^(+)T cells

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Cellular & Molecular Immunology 2023年第7期20卷 777-793页

作者： Yuwei Hao Bahar Miraghazadeh rochna Chand ainsley r.davies Chelisa Cardinez Kristy Kwong Morgan B.Downes rebecca A.Sweet Pablo F.Cañete Lloyd J.D’Orsogna David A.Fulcher Sharon Choo Desmond Yip Geoffrey Peters Sonia Yip Matthew J.Witney Maxim Nekrasov Zhi-Ping Feng David C.Tscharke Carola G.Vinuesa Matthew C.Cook Centre for Personalised Immunology John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia Translational research Unit The Canberra HospitalCanberraACTAustralia Division of Immunology and Infectious Diseases John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia Department of Immunology Fiona Stanley HospitalPerthWAAustralia Department of Immunology The Royal Children’s HospitalMelbourneVICAustralia Department of Medical Oncology The Canberra HospitalCanberraACTAustralia ANU Medical School The Australian National UniversityCanberraACTAustralia NHMrC Clinical Trials Unit The University of SydneySydneyNSWAustralia The ACrF Biomolecular resource Facility John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia ANU Bioinformatics Consultancy John Curtin School of Medical ResearchThe Australian National UniversityCanberraACTAustralia Francis Crick Institute 1 Midland RdLondon NW11ATUK Cambridge Institute of Therapeutic Immunology and Infectious Disease University of CambridgeCambridgeUnited Kingdom.

As chronic antigenic stimulation from infection and autoimmunity is a feature of primary antibody deficiency(PAD),analysis of affected patients could yield insights into T-cell differentiation and explain how environmental exposures modify clinical phenotypes conferred by single-gene defects.CD57 marks dysfunctional T cells that have differentiated after antigenic stimulation.Indeed,while circulating CD57^(+)CD4^(+)T cells are normally rare,we found that they are increased in patients with PAD and markedly increased with CTLA4 haploinsufficiency or blockade.We performed single-cell rNA-seq analysis of matched CD57^(+)CD4^(+)T cells from blood and tonsil samples.Circulating CD57^(+)CD4^(+)T cells(CD4cyt)exhibited a cytotoxic transcriptome similar to that of CD8^(+)effector cells,could kill B cells,and inhibited B-cell responses.CTLA4 restrained the formation of CD4cyt.While CD57 also marked an abundant subset of follicular helper T cells,which is consistent with their antigen-driven differentiation,this subset had a preexhaustion transcriptomic signature marked by TCF7,TOX,and ID3 expression and constitutive expression of CTLA4 and did not become cytotoxic even after CTLA4 inhibition.Thus,CD57^(+)CD4^(+)T-cell cytotoxicity and exhaustion phenotypes are compartmentalised between blood and germinal centers.CTLA4 is a key modifier of CD4^(+)T-cell cytotoxicity,and the pathological CD4cyt phenotype is accentuated by infection.

关键词： CTLA4 Immunodeficiency Cell exhaustion Terminal differentiation Cytotoxic CD4^(+)T cells CD57

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Biochemical and Molecular Epidemiology of Cancer

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Biomedical and Environmental Sciences 1991年第1期4卷 73-92页

作者： HArUHIKO SUGIMUrA ainsley WESTON NEIL E.CAPOrASO PETEr G.SHIELDS ELISE D.BOWMAN rOBErT A.METCALF CUrTIS C.HArrIS Laboratory of Human Carcinogenesis Laboratory of Human CarcinogenesisEnvironmental Epidemiology Branch National Cancer Institute National Institutes of HealthLaboratory of Human CarcinogenesisLaboratory of Human CarcinogenesisLaboratory of Human CarcinogenesisLaboratory of Human Carcinogenesis Rockville Maryland 20892

Examples of practical approaches to molecular epidemiology of human cancer are described. Biomarkers of carcinogen exposure or inherited host factors for cancer susceptibility are discussed. Major advances have been made in the detection of carcinogen-macromolecular adducts through the use of high performance liquid chromatography, immunoaffinity chromatography, the 32P-postlabeling assay, enzyme immunoassays, gas chromatography/mass spectroscopy and synchronous spectrophotofluorimetry. The polycyclic aromatic hydrocarbon- DNA adducts are the most extensively studied in this field and together with antibodies to these adducts found in human serum, they have become useful indicators of exposure to carcinogens. Assays for various kinds of alky 1-DNA adducts have also been developed and the presence of these adducts have been documented in human tissues. Carcinogen-protein adducts have proven to be useful molecular dosimeters of carcinogen exposure. For example, 4-aminobiphenyl hemoglobin adducts are highly correlated with exposure to tobacco smoke. The study of the molecular aspects of interindividual differences in the metabolism and activation of xenobiotics and other genetic markers [DNA-restriction fragment length polymorphisms (rFLPs), mutations, and functional loss of specific genes in carcinogenesis] is an emerging new field that is discussed in the context of genetic susceptibility to cancer. The cytochrome P450 phenotypes and acetylation phenotype are examples of genetic markers that indicate an individual's potential for metabolism of exogenous substances. Further, inherited genetic polymorphic markers, e.g., DNA-rFLPs at protooncogene loci (HrAS-1 and L-myc) have been examined in a case-control study of lung cancer. Data concerning mutations of protooncogenes (H-, K-, and N-rAS) and tumor suppressor genes (retinoblastoma and p53 genes) in various common cancers are providing evidence of multiple genetic lesions that occur during the multistage process of carcinogenesis.

关键词： gene DNA Biochemical and Molecular Epidemiology of Cancer

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大型接地体性能的试验研究(英文)

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高电压技术 2011年第11期37卷 2733-2738页

作者： D. Guo D. Lathi H. Griffiths N. Harid A. ainsley A. Haddad National Grid Warwick UK High Voltage Energy Systems Group Cardiff University Cardiff UK

Analytical and numerical simulation techniques have been developed for the calculation of earth resistance/ impedance and to estimate the potential distribution in the vicinity of earth electrodes.However,very little literature is available on experimental validation of these calculation techniques.To address this,a programme of experimental tests on various earth electrodes has been carried out at the lower water reservoir of a hydro pumped-storage power station in North Wales.In this paper,the earthing test facility at Dinorwig power station is described including the details of the experimental set up.The results from experimental tests on a 5 mX5 m earth grid,immersed in water and energized under ac,dc and impulse,are presented.The values of measured earth resistance/impedance and water surface potential distributions are compared with those obtained from analytical calculations and detailed numerical computer simulations.

关键词： earthing systems earth impedance resistivity surface potential distribution

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斯坦福最具人气课程（英文）

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大学英语 2015年第7期 33-39页

作者： ainsley O’Connell 扬帆

在美国名校斯坦福大学,最受欢迎的课程居然不是＂计算机科学＂,而是一门更为重要的课程——＂设计你的人生＂!Before Kanyi Maqubela became an investment partner at the Collaborative Fund,an early-stage venture capital firm foc... 详细信息

关键词：课程 capital 人气 Before 斯坦福大学计算机科学 the 名校

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全球知识经济背景下的西澳州产业政策的方向——致西澳州技术与产业咨询委员会的报告

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经济资料译丛 2007年第4期 93-96页

作者： John Houghton ainsley Jolley ron Johnson Peter Morris 罗志凯紫金矿业公司邮政编码364000

本研究的出发点是实际上全球化和朝以知识为基础的经济转移正在推动世界经济的性质和结构的改变。经济活动的知识密集度的提高和经济事务的日益全球化正推动着影响到每一个行业、厂商、个人和地区的普遍改变.

关键词：经济背景产业政策咨询委员会知识澳州技术世界经济经济事务

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