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：
SUZANNE L. CASSEL
金额：
$ 61.88万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/10707832
关键词：
AKT1 gene Affect Antigen-Presenting Cells Antiviral Response Apoptosis Area Autoimmune Diseases Automobile Driving Binding CASP1 gene CD4 Positive T Lymphocytes Cell Communication Cell Death Cells Clinical Coculture Techniques Complex Data Dendritic Cells Down-Regulation Evaluation Family Family member Generations Gram-Negative Bacteria Growth IL18 gene Immune Immune Evasion Immune checkpoint inhibitor Immune response Immune signaling Impairment In Vitro Induction of Apoptosis Inflammasome Inflammatory Influenza Influenza A virus Innate Immune Response Innate Immune System Leucine-Rich Repeat Ligands Macrophage Maintenance Mediating Melanoma Cell Modeling Morbidity - disease rate Mus Myeloid Cells Neoplasm Metastasis Nucleotides Organ Transplantation Pathogenicity Pathology Pathway interactions Pattern recognition receptor Phosphorylation Physiological Play Proteins Regulation Role Signal Pathway Signal Transduction T cell regulation T cell response T-Lymphocyte T-Lymphocyte Subsets Treatment Efficacy Tumor Necrosis Factor Ligand Superfamily Member 6 Up-Regulation Viral Virus Diseases adaptive immune response adverse outcome cell injury combat cytokine effector T cell human disease immunogenic improved in vivo Model influenza infection innate immune pathways insight melanoma member microbial products mortality mouse model new therapeutic target novel novel strategies pathogen prevent receptor response side effect subcutaneous technological innovation transcriptome tumor tumor growth tumor 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.

项目摘要 NLRC4是核苷酸结合结构域和富含亮氨酸的重复受体（NLR）家族的成员胞质模式识别受体，主要在先天免疫细胞中表达。规范NLRC4 在通过NAIP蛋白识别革兰氏阴性细菌成分后，途径被激活导致NLRC4寡聚和炎症体复合物的组装。 NLRC4的激活炎性小体在caspase-1介导的加工和促炎性细胞因子IL-的释放中达到顶点 1。我们发现NLRC4在用任何B16F10皮下挑战的小鼠中起受保护的作用黑色素瘤细胞或影响病毒感染的模型。在这两种模型中，NLRC4缺陷型（NLRC4 - / - ）小鼠均具有效应子CD4+ T细胞的丧失。强大的T细胞反应的生成和维护取决于T细胞的相互作用与抗原呈现细胞。 NLRC4 - / - 巨噬细胞和树突状细胞（DC）的评估显示 AKT1和FOXO3A磷酸化的下调，这又导致凋亡的上调在NLRC4 - / - 髓样细胞上诱导配体FASL，该细胞引发了共培养的T细胞中细胞死亡。重要的是，与众不同 NLRC4的规范NLRC4途径，抗肿瘤和抗病毒作用是炎性症的独立的，提出了一种新型的非典型NLRC4信号通路。在这个建议中，我们将扩大这些小说发现并利用创新技术来探讨未解决的问题。我们假设该内源性危险信号信号激活髓样细胞中的NLRC4，进而通过防止效应T细胞反应保持 FASL上调。我们将定义NLRC4在抗原存在的细胞和 NLRC4通过该途径修饰了随后的T细胞反应的新型非经典途径。我们也会确定哪些因素下调了NLRC4表达的表达以及如何探索该下调病原体和肿瘤。这些研究将确定可以针对的先天免疫细胞中的新途径增强特异性抗肿瘤或抗病毒反应或抑制致病性T细胞反应。