Innate NLRC4 signaling controls adaptive immune responses

先天 NLRC4 信号控制适应性免疫反应

• 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
• 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

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NLRC4的核苷酸结合区和富亮氨酸重复序列受体(NLR)家族的成员。 胞浆模式识别受体，主要表达于先天免疫细胞。规范的NLRC4 NAIP蛋白识别革兰氏阴性菌组分后激活通路 导致NLRC4齐聚和炎症体复合体的组装。NLRC4的激活 炎症小体在caspase-1介导的促炎症细胞因子IL-1的处理和释放中达到顶峰 1个。我们发现NLRC4在B16F10或B16F10皮下攻击的小鼠中起到保护作用 黑色素瘤细胞或甲型流感病毒感染模型。在这两种模型中，NLRC4缺陷(NLRC4-/-)小鼠都有 失去效应的CD4+T细胞。T细胞反应的产生和维持依赖于T细胞的相互作用 有抗原提呈细胞。对NLRC4-/-巨噬细胞和树突状细胞(DC)的评估显示 下调AKT1和FOXO3a的磷酸化，进而导致细胞凋亡上调- 在NLRC4-/-髓系细胞上诱导配体FasL，从而引发共培养的T细胞死亡。重要的是，不同于 典型的NLRC4途径、抗肿瘤和抗病毒作用是非炎症性的， 提示了一种新的非典型NLRC4信号通路。在这项提议中，我们将对这些小说进行扩展。 发现并利用创新技术探索悬而未决的问题。我们假设内生性 危险信号激活髓系细胞中的NLRC4，进而通过阻止 FasL上调。我们将确定NLRC4在抗原提呈细胞中被激活的机制和 NLRC4修饰随后的T细胞反应的新的非规范途径。我们还将 确定哪些因素下调NLRC4的表达，以及如何利用这种下调 病原体和肿瘤。这些研究将确定先天免疫细胞中可被靶向的新途径 增强特异性抗肿瘤或抗病毒反应或抑制致病T细胞反应。