IL-10/IL10R in the Regulation of Self-Reactive CTL by CD8+ T-cells
IL-10/IL10R 在 CD8 T 细胞调节自身反应性 CTL 中的作用
基本信息
- 批准号:9223809
- 负责人:
- 金额:$ 23.85万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-06 至 2018-11-30
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdoptive TransferAnimalsAntigen PresentationAntigensAutoimmune DiseasesAutoimmune ProcessAutoimmunityCD8-Positive T-LymphocytesCD8B1 geneCancer PatientCell LineageCell physiologyCellsCellular ImmunityCharacteristicsChickensComplexCytotoxic T-LymphocytesDendritic CellsDevelopmentEffector CellElementsEnvironmentEquilibriumExperimental ModelsFamily PicornaviridaeFutureGene ExpressionGenerationsGeneticGoalsHomeostasisIL10 geneIL2 geneImmuneImmune responseImmune systemImmunityImmunocompetentImmunosuppressionInflammationInflammatoryInformal Social ControlInsulinInterferon Type IIInterleukin-10InvestigationKnowledgeLearningMaintenanceMalignant NeoplasmsMature T-LymphocyteMediatingMemoryModelingMolecularMusOVA-8OvalbuminPancreasPancreatic InjuryPatientsPhenotypePlayPopulationProcessProductionProtocols documentationRattusRecruitment ActivityRegulationRegulatory T-LymphocyteReporterReportingResolutionRoleSchemeSourceSpleenStructureSuppressor-Effector T-LymphocytesSurfaceSystemT-Cell Antigen Receptor SpecificityT-Cell ReceptorT-LymphocyteTestingTherapeuticTissuesTransgenesVaccinationVirusWorkautoreactivitybasecell growthcellular targetingcytokinecytotoxicityimmune system functionimmunoregulationin vitro Modelin vivoinsightkillingsperforinphenotypic biomarkerpromoterreceptorresponsevector-induced
项目摘要
PROJECT SUMMARY/ABSTRACT
CD8+ suppressor T-cells play important roles in the maintenance of immune homeostasis. However, the
phenotypic and functional characteristics of these cells remains poorly characterized relative to their CD4
regulatory T cell counterparts, even though some evidence suggests CD8 regulators can be more important
than CD4 T regulatory cells. We have been investigating the cellular determinants limiting autoimmune attack
in mice against otherwise healthy tissue by introducing and activating self-reactive T cells into a normally
tolerant and regulated environment. A key finding is that inflammation in the tissue is quickly extinguished
limiting cellular damage to vital structures. Early in the inflammatory process immune cells from the tolerant
repertoire are recruited into the tissues harboring autoimmune CTL. Using genetic depletion strategies, we
learned that CD8+ regulators are more critical to limiting autoimmune attack in this setting than are CD4+
regulators. Importantly, regulation can be restored in our model by adoptive transfer of CD8+ spleen cells from
otherwise unmanipulated animals. This approach identified IL10 and perforin as critical factors determining the
ability to limit the damage by autoimmune attack. However, we failed to find evidence of IL10 gene expression
the CD8 “regulatory” cell population in inflamed tissue using an IL10 reporter suggesting that IL10 may act
earlier in the process. Furthermore, we found that fixing the T cell receptor specificity of the regulatory
population did not ablate their ability to limit autoimmune attack. Accordingly, we have developed the
overarching hypothesis that IL10 is essential for the generation of CD8+ suppressor cells and that the
mechanism of suppression is through a perforin-dependent killing or inactivation of antigen specific effector T-
cells mediated through a TcR independent recognition process. In this study, we seek to acquire needed
fundamental information about the role IL10 in the generation and function of CD8 regulatory T cells. Our
approach will be to (1) identify the cellular surface phenotypic markers associated with the regulatory cells, (2)
identify important sources of IL10 in the generation and function of these CD8 regulatory T cells, and (3) learn
where and when these regulatory cells are formed. Along the way we will examine alternative in vitro models
to enable efficient definition of the molecular mechanisms giving rise to CD8 regulators and to their ability to
limit the functions of activated CTL. Understanding the basis of this strong immune regulatory function could
provide insights into how to augment or limit CTL attack for the benefit of cancer or autoimmune disease
patients, respectively.
项目总结/文摘
项目成果
期刊论文数量(0)
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{{ truncateString('LARRY R PEASE', 18)}}的其他基金
Blocking airway inflammation with B7-DC cross-linking Ab
使用 B7-DC 交联抗体阻断气道炎症
- 批准号:
7036883 - 财政年份:2006
- 资助金额:
$ 23.85万 - 项目类别:
Blocking airway inflammation with B7-DC cross-linking Ab
使用 B7-DC 交联抗体阻断气道炎症
- 批准号:
7166813 - 财政年份:2006
- 资助金额:
$ 23.85万 - 项目类别:
Blocking airway inflammation with B7-DC cross-linking Ab
使用 B7-DC 交联抗体阻断气道炎症
- 批准号:
7331495 - 财政年份:2006
- 资助金额:
$ 23.85万 - 项目类别:
Blocking airway inflammation with B7-DC cross-linking Ab
使用 B7-DC 交联抗体阻断气道炎症
- 批准号:
7544476 - 财政年份:2006
- 资助金额:
$ 23.85万 - 项目类别:
Promoting Tumor Immunity by Cross-Linking B7-DC
通过交联 B7-DC 促进肿瘤免疫
- 批准号:
7176218 - 财政年份:2004
- 资助金额:
$ 23.85万 - 项目类别:
Promoting Tumor Immunity by Cross-linking B7-DC
通过交联 B7-DC 促进肿瘤免疫
- 批准号:
8387014 - 财政年份:2004
- 资助金额:
$ 23.85万 - 项目类别:
Promoting Tumor Immunity by Cross-linking B7-DC
通过交联 B7-DC 促进肿瘤免疫
- 批准号:
7577266 - 财政年份:2004
- 资助金额:
$ 23.85万 - 项目类别:
Promoting Tumor Immunity by Cross-Linking B7-DC
通过交联 B7-DC 促进肿瘤免疫
- 批准号:
6859413 - 财政年份:2004
- 资助金额:
$ 23.85万 - 项目类别:
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