Innate NLRC4 signaling controls adaptive immune responses
先天 NLRC4 信号控制适应性免疫反应
基本信息
- 批准号:10707832
- 负责人:
- 金额:$ 61.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-20 至 2028-05-31
- 项目状态:未结题
- 来源:
- 关键词:AKT1 geneAffectAntigen-Presenting CellsAntiviral ResponseApoptosisAreaAutoimmune DiseasesAutomobile DrivingBindingCASP1 geneCD4 Positive T LymphocytesCell CommunicationCell DeathCellsClinicalCoculture TechniquesComplexDataDendritic CellsDown-RegulationEvaluationFamilyFamily memberGenerationsGram-Negative BacteriaGrowthIL18 geneImmuneImmune EvasionImmune checkpoint inhibitorImmune responseImmune signalingImpairmentIn VitroInduction of ApoptosisInflammasomeInflammatoryInfluenzaInfluenza A virusInnate Immune ResponseInnate Immune SystemLeucine-Rich RepeatLigandsMacrophageMaintenanceMediatingMelanoma CellModelingMorbidity - disease rateMusMyeloid CellsNeoplasm MetastasisNucleotidesOrgan TransplantationPathogenicityPathologyPathway interactionsPattern recognition receptorPhosphorylationPhysiologicalPlayProteinsRegulationRoleSignal PathwaySignal TransductionT cell regulationT cell responseT-LymphocyteT-Lymphocyte SubsetsTreatment EfficacyTumor Necrosis Factor Ligand Superfamily Member 6Up-RegulationViralVirus Diseasesadaptive immune responseadverse outcomecell injurycombatcytokineeffector T cellhuman diseaseimmunogenicimprovedin vivo Modelinfluenza infectioninnate immune pathwaysinsightmelanomamembermicrobial productsmortalitymouse modelnew therapeutic targetnovelnovel strategiespathogenpreventreceptorresponseside effectsubcutaneoustechnological innovationtranscriptometumortumor growthtumor progression
项目摘要
Project Summary
NLRC4 is a member of the Nucleotide-Binding Domain and Leucine-Rich Repeat Receptor (NLR) family of
cytosolic pattern recognition receptors and is primarily expressed in innate immune cells. The canonical NLRC4
pathway is activated following the recognition of components of Gram-negative bacteria by NAIP proteins
resulting in NLRC4 oligomerization and assembly of the inflammasome complex. Activation of the NLRC4
inflammasome culminates in caspase-1-mediated processing and release of the pro-inflammatory cytokine IL-
1. We have found that NLRC4 plays a protective role in mice challenged subcutaneously with either B16F10
melanoma cells or in a model of influenza A virus infection. In both models, Nlrc4-deficient (Nlrc4-/-) mice had a
loss of effector CD4+ T cells. Generation and maintenance of robust T cell responses relies on T cell interactions
with antigen presenting cells. Evaluation of Nlrc4-/- macrophages and dendritic cells (DC) revealed a
downregulation of AKT1 and FoxO3a phosphorylation, which in turn resulted in the upregulation of the apoptosis-
inducing ligand FasL on Nlrc4-/- myeloid cells that triggered cell death in co-cultured T cells. Importantly, unlike
the canonical NLRC4 pathway, the anti-tumor and anti-viral roles of NLRC4 were inflammasome-independent,
suggesting a novel non-canonical NLRC4 signaling pathway. In this proposal we will expand on these novel
findings and utilize innovate technologies to probe unanswered questions. We hypothesize that endogenous
danger signals activate NLRC4 in myeloid cell, which in turn maintains effector T cell responses by preventing
FasL upregulation. We will define the mechanism by which NLRC4 is activated in antigen presenting cells and
the novel non-canonical pathway through which NLRC4 modifies subsequent T cell responses. We will also
determine what factors downregulate NLRC4 expression and how this downregulation can be exploited by
pathogens and tumors. These studies will identify novel pathways in innate immune cells that can be targeted to
either augment specific anti-tumor or anti-viral responses or inhibit pathogenic T cell responses.
项目总结
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)
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SUZANNE L. CASSEL其他文献
SUZANNE L. CASSEL的其他文献
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{{ truncateString('SUZANNE L. CASSEL', 18)}}的其他基金
Mechanisms of NIrp3 inflammasome activation by mitochondrial dysfunction
线粒体功能障碍激活 NIrp3 炎症小体的机制
- 批准号:
9392881 - 财政年份:2013
- 资助金额:
$ 61.88万 - 项目类别:
Mechanism of Nlrp3 inflammasome activation by mitochondrial dysfunction
线粒体功能障碍激活Nlrp3炎症小体的机制
- 批准号:
8628607 - 财政年份:2013
- 资助金额:
$ 61.88万 - 项目类别:
Mechanism of Nlrp3 inflammasome activation by mitochondrial dysfunction
线粒体功能障碍激活Nlrp3炎症小体的机制
- 批准号:
8773574 - 财政年份:2013
- 资助金额:
$ 61.88万 - 项目类别:
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