Lymphocyte Dynamics
淋巴细胞动力学
基本信息
- 批准号:8946366
- 负责人:
- 金额:$ 99.94万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AdjuvantAgeAntigensBlastomycesCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCell CountCellsCessation of lifeComplexComputational BiologyEmigrantFrequenciesGenesGoalsHIVHIV InfectionsHeatingHomeostasisIL2RA geneImmune responseImmunizationIndividualInfectionInterferon Type IInterleukin-1Interleukin-10Interleukin-12Interleukin-17Knock-outLeadLifeLigandsListeria monocytogenesLiverLungLymphocyteLymphocyte CountLymphocytic choriomeningitis virusMeasurementMeasuresMediatingMemoryMolecularMusNR4A1 geneNatural Killer CellsNeonatalPatternPeptide/MHC ComplexPeptidesPeripheralPhenotypePhysiologicalPopulationProcessProductionProliferatingProteinsRNARecording of previous eventsRegimenRegulationRelative (related person)RoleSIVSelf StimulationSeriesSpecificityT cell responseT-Cell DepletionT-Cell ProliferationT-LymphocyteTLR3 geneTimeTissuesTransgenic OrganismsVaccinesVacciniaVacciniumantigen challengebasecytokinegranzyme Bin vivoinsightinterdisciplinary approachkillingslymphocyte proliferationmemory CD4 T lymphocytemigrationpathogenreceptorresponsetool development
项目摘要
Lymphocyte numbers are regulated both by responses to conventional exogenous antigens and endogenous microflora, by stimulation by self-peptide/MHC complexes and by the action of a series of cytokines. This multifaceted regulation permits individuals to maintain a broad repertoire of lymphocytes of distinctive specificities, allowing responses against a vast array of foreign substances and, at the same time, providing a pattern of memory based on the immunization history of the individual. The study of the process of lymphocyte dynamics that underlies this regulation requires a multidisciplinary approach, aimed both at the molecular underpinnings of the processes through which lymphocytes survive and proliferate and a systemics/ computational biology approach to appreciate the overall mechanisms governing total numbers of lymphocytes of distinct phenotype and distinct specificity. Emphasis has been placed on four aspects of this problem: the priming, expansion and differentiated phenotype of naive CD4 T cells in response to antigen challenge, the dynamics of lymphocyte memory and of memory phenotype cells, the mechanisms underlying CD4 T cell depletion in HIV infection, and the process of homeostatic proliferation and death.
In an effort to develop strategies to enhance response of nave and memory cells to their cognate antigens, it was observed that the most potent stimulant of such expansion was the cytokine IL-1. When expansion of CD4 TCR transgenic T cells in a syngeneic host in response to antigen was measured, it was found that administering IL-1 over a 3 to 5 day period caused a ten-fold or greater enhancement in the degree of expansion when compared to that seen using conventional adjuvants such as LPS. This was equally true for naive and memory cells and was not mediated by other cytokines. The effect could only be partially explained by enhanced proliferation so that greater survival was also implicated. The use of recipients that were IL-1 receptor knockouts and IL-1 receptor-sufficient donors of TCR transgenic T cells showed that IL-1 could act directly on the responding CD4 or CD8 T cells to mediate expansion. The IL-1 receptor antagonist diminished the adjuvant effect of LPS indicating that a substantial portion of the effect of this conventional adjuvant was due to endogenous production of IL-1. Initial analysis of genes activated and suppressed in cells responding to antigen in the presence of LPS suggest avenues for further analysis that may lead to a mechanistic understanding of the IL-1 effect. The very robust effect of IL-1 suggests it may have a role in certain immunization strategies.
IL-1 acts directly on CD4 T cells to enhance their differentiation into IL-17 producing cells. However, although IL-1 acts directly on CD8 cells to mediate their expansion, differentiation of CD8 into efficient cytotoxic cells requires the action of IL-1 on non T cells. IL-1 strikingly enhances the frequency of effector/memory CD8 T cells that migrate into peripheral tissues such as lung and liver. Such migration requires expression of IL-1R1 on a cell other than the responding T cells. Strikingly, the effects of IL-1 during priming are retained at the time of secondary challenge even though IL-1 is not administered again. Thus, the secondary response in mice primed in the presence of IL-1 includes increased in numbers of antigen-specific effector CD8 T cells, a greater presence in the tissues, and the expression of large amounts of granzyme B.
Administration of IL-1 with weak vaccines, such as heat killed Listeria monocytogenes, the gD2 protein of H. simplex, heat killed Blastomyces or peptides associated with vaccinia, result strikingly enhances their protective capacity.
Memory CD4 T cell proliferation was shown to be quite slow. Specific T cells from mice infected with LCMV divide at a rate of <2% per day. By contrast CD44bright CD25- CD4 T cells divide much more rapidly, at 8 to 10% per day. This rapid steady state proliferation of "memory phenotype" CD4 T cells is similar in conventional and germfree mice. Analysis of the repertoire of memory phenotype undergoing proliferation revealed no difference in receptor complexity from that of non-dividing memory phenotype cells. This implies that division is largely stochastic and probably dominantly driven by cytokines or other endogenous ligands rather than by peptide/ MHC complexes, whether of exogenous or endogenous origin.
Memory phenotype and authentic memory cells differ from one another not only in their proliferative rates but, based on an RNA-SEQ analysis, also on the expression of NUR77, the latter being highly expressed on authentic memory cells even 30 days after priming, when they are already quiescent. Interestingly, in neonatal mice, the memory phenotype pool is efficiently colonized and preliminary results suggests that after 2 weeks of age, thymic emigrants enter the pool very inefficiently. We suspect then that the memory phenotype pool represents a set of self-specific cells generated early in the life of the individual and capable of producing Th1, Th2 or Th17 type cytokines early in infections as a results of stimulation of these cells through key cytokines, self-peptide mHC complexes or a combination of the two. In a sense, these cells are adaptive Th cells with a potent innate functionallity
Efforts to understand the role of distinct priming regimens to induce particular phenotypic CD4 T cells responses to lung immunization reveal a profound effect of different "adjuvants". Priming in the presence of LPS leads to a TH17 response whereas priming in the presence of polyI:C to an exclusive IFNgamma response. Based on studies with KO mice, the results have been interpreted as indicated that LPS, through its activation of Myd88, results in robust IL-10 production, blocking IL-12 production and Th1 priming. In parallel, though its activation of TRIF/TRAM, LPS activates IL-1 production, markedly enhancing Th17 priming. By contrast, polyI:C, acting through TLR3 and TRIF activates type I interferon and IL-12, enhancing IFNgamma priming and blocking Th17 induction. These results give important insight into the precise regulation of CD4 T cells responses to distinct pathogens in the lung.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
William Paul其他文献
William Paul的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('William Paul', 18)}}的其他基金
Analyzing Cytokine- and TCR-Mediated Lymphocyte Responses by RNAi
通过 RNAi 分析细胞因子和 TCR 介导的淋巴细胞反应
- 批准号:
8745429 - 财政年份:
- 资助金额:
$ 99.94万 - 项目类别:
Analyzing Cytokine- and TCR-Mediated Lymphocyte Responses by RNAi
通过 RNAi 分析细胞因子和 TCR 介导的淋巴细胞反应
- 批准号:
7592323 - 财政年份:
- 资助金额:
$ 99.94万 - 项目类别:
Analyzing Cytokine- and TCR-Mediated Lymphocyte Responses by RNAi
通过 RNAi 分析细胞因子和 TCR 介导的淋巴细胞反应
- 批准号:
8555902 - 财政年份:
- 资助金额:
$ 99.94万 - 项目类别:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:n/a
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
- 批准号:
2341426 - 财政年份:2024
- 资助金额:
$ 99.94万 - 项目类别:
Continuing Grant
Collaborative Research: Resolving the LGM ventilation age conundrum: New radiocarbon records from high sedimentation rate sites in the deep western Pacific
合作研究:解决LGM通风年龄难题:西太平洋深部高沉降率地点的新放射性碳记录
- 批准号:
2341424 - 财政年份:2024
- 资助金额:
$ 99.94万 - 项目类别:
Continuing Grant
PROTEMO: Emotional Dynamics Of Protective Policies In An Age Of Insecurity
PROTEMO:不安全时代保护政策的情绪动态
- 批准号:
10108433 - 财政年份:2024
- 资助金额:
$ 99.94万 - 项目类别:
EU-Funded
The role of dietary and blood proteins in the prevention and development of major age-related diseases
膳食和血液蛋白在预防和发展主要与年龄相关的疾病中的作用
- 批准号:
MR/X032809/1 - 财政年份:2024
- 资助金额:
$ 99.94万 - 项目类别:
Fellowship
Atomic Anxiety in the New Nuclear Age: How Can Arms Control and Disarmament Reduce the Risk of Nuclear War?
新核时代的原子焦虑:军控与裁军如何降低核战争风险?
- 批准号:
MR/X034690/1 - 财政年份:2024
- 资助金额:
$ 99.94万 - 项目类别:
Fellowship
Walkability and health-related quality of life in Age-Friendly Cities (AFCs) across Japan and the Asia-Pacific
日本和亚太地区老年友好城市 (AFC) 的步行适宜性和与健康相关的生活质量
- 批准号:
24K13490 - 财政年份:2024
- 资助金额:
$ 99.94万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Discovering the (R)Evolution of EurAsian Steppe Metallurgy: Social and environmental impact of the Bronze Age steppes metal-driven economy
发现欧亚草原冶金的(R)演变:青铜时代草原金属驱动型经济的社会和环境影响
- 批准号:
EP/Z00022X/1 - 财政年份:2024
- 资助金额:
$ 99.94万 - 项目类别:
Research Grant
ICF: Neutrophils and cellular senescence: A vicious circle promoting age-related disease.
ICF:中性粒细胞和细胞衰老:促进与年龄相关疾病的恶性循环。
- 批准号:
MR/Y003365/1 - 财政年份:2024
- 资助金额:
$ 99.94万 - 项目类别:
Research Grant
Doctoral Dissertation Research: Effects of age of acquisition in emerging sign languages
博士论文研究:新兴手语习得年龄的影响
- 批准号:
2335955 - 财政年份:2024
- 资助金额:
$ 99.94万 - 项目类别:
Standard Grant
Shaping Competition in the Digital Age (SCiDA) - Principles, tools and institutions of digital regulation in the UK, Germany and the EU
塑造数字时代的竞争 (SCiDA) - 英国、德国和欧盟的数字监管原则、工具和机构
- 批准号:
AH/Y007549/1 - 财政年份:2024
- 资助金额:
$ 99.94万 - 项目类别:
Research Grant