Innate DC Govern TH Polarization through the Novel Regulator AIMp1

通过新型调节器 AIMp1 固有直流控制 TH 极化

• 批准号: 10605267
• 负责人: WILLIAM Karl DECKER
• 金额: $ 56.34万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605267
• 关键词: Ablation; Adoptive Transfer; Alleles; Animals; Antitumor Response; Attenuated Vaccines; Autoimmune Diseases; Back; Binding; Bioinformatics; Biological; Blocking Antibodies; Bone Marrow; Cell physiology; Cells; Cellular Immunity; Circulation; Clinical; Communicable Diseases; Complex; Cues; DUSP1 gene; Data; Data Set; Dedications; Defect; Dendritic Cells; Detection; Diagnosis; Disease; Drug Design; Effector Cell; Elements; Exhibits; FOS gene; Formulation; Functional disorder; Gene Expression Profiling; Gene Expression Regulation; Generations; Genetic; Genomics; Health; Helper-Inducer T-Lymphocyte; Heterodimerization; Human; IL12A gene; ITGAM gene; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunocompromised Host; In Vitro; Individual; Infection; Influenza; Interferon Type II; Interleukin-12; Intervention; Knockout Mice; Lung; Maintenance; Malignant Neoplasms; Mediating; Mus; Myelogenous; Natural Immunity; Pathway interactions; Patients; Peripheral; Personal Satisfaction; Pharmacologic Substance; Phase; Phenotype; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Play; Population; Primary Neoplasm; Process; Production; Prophylactic treatment; Protein Array; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Recombinant Proteins; Role; Sampling; Signal Induction; Signal Transduction; Specificity; Spleen; T cell response; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; The Cancer Genome Atlas; Tissues; Transcription Factor AP-1; Tumor Antigens; Tumor Immunity; Up-Regulation; Vaccination; Vaccines; Viral; Virus; Virus Diseases; Work; adaptive immune response; anti-tumor immune response; arm; cancer therapy; cell type; cytokine; druggable target; gene product; genetic signature; human disease; immune function; immunoregulation; in vivo; influenza infection; interleukin-12 receptor; lymph nodes; mouse model; new therapeutic target; next generation; novel; novel vaccines; p38 Mitogen Activated Protein Kinase; pathogen; pharmacologic; polarized cell; response; transcriptome sequencing; tumor; vaccination strategy

Abstract The inability to generate effective cell-mediated immunity outside the context of live virus vaccination continues to be a pervasive clinical problem for vaccination of immunocompromised individuals, cell-mediated prophylaxis of viral diseases for which no live vaccines exist, and critically, the generation of durable antitumor immune responses. Cell mediated immunity is initiated by dendritic cells (DC), a critical lineage of innate immunity that serves as the principal point of contact and crosstalk between the innate and adaptive arms of the immune system. Successful response to pathogen requires that DC detect and integrate a broad array of environmental cues to exact control over critical downstream responses, particularly T-helper (TH) cell polarization. Many such cues, as well as mechanisms of detection and integration, remain to be understood. In this proposal we will interrogate the emerging but well-supported hypothesis that DC expression of the novel regulator AIMp1 drives physiologic propagation of TH1 cellular immunity. This hypothesis is based upon extensive and rigorous data demonstrating that genetic ablation of AIMp1 produces deficits in TH1 polarization significantly more profound than those characterized in IL-12 or IL-12R-deficient mice. AIMp1 knockout mice lose the ability to mount an adaptive immune response against influenza, exhibiting complete lethality to a normally sublethal challenge, deficient HA-specific IgG2a production, and loss of nearly all IFN-g-secreting T-cells in the lung by post-infection day 15. AIMp1-/- animals also exhibited complete loss of antitumor immunity that could be rescued by adoptive transfer of wildtype DC. Mechanistically, the data suggest these deficits are due to defective p38MAPK activation in AIMp1-/- DC with downstream dysregulation of AP-1 heterodimerization. Direct relevance of AIMp1 to human disease was validated through a pan-cancer TCGA bioinformatics analysis of 9,000 primary human tumor sam- ples, revealing an unexpected 70% survival advantage among patients expressing elevated levels of AIMp1 in the primary tumor. In this dataset, elevated AIMp1 expression was highly correlated with an activated DC gene signature and TH1 immune profile. Strikingly, this survival advantage was not recapitulated among patients in which the primary tumor exhibited high levels of IL-12A (p35) expression. These data suggest an unrecognized yet indispensable role for DC-expressed AIMp1 in adaptive TH1 governance and provide a cogent rationale for this study: confirmation that a novel regulatory factor is essential for integration and transduction of TH1-inducing signals in DC will alter the paradigm by which TH1 immune signaling is presently understood. The mechanisms through which AIMp1 governs cellular immunity will be determined by the completion of three specific aims. In aim I we will define the in vivo DC subset(s) for which AIMp1 function is critical to propagation of TH1 immunity. In aim II we will define the manner by which AIMp1 interfaces with the DC regulatory signaling cascade. In aim III we will define deficits in effector cell function that result from conditional loss of AIMp1 in DC populations. In all aims, differences between AIMp1-deficiency and IL-12 deficiency will be characterized where appropriate.

抽象的 在实时病毒疫苗接种背景之外产生有效的细胞介导的免疫力的无法继续 为了成为免疫功能低下个体疫苗接种的普遍临床问题，细胞介导的预防 不存在无活疫苗的病毒疾病，并且批判性地产生了耐用的抗肿瘤免疫 回答。细胞介导的免疫力是由树突状细胞（DC）引发的，这是一种先天免疫的临界谱系，是 作为免疫的先天和适应性臂之间的接触和串扰的主要点 系统。对病原体的成功反应需要DC检测并整合一系列的环境 提示精确控制关键下游反应，尤其是T-辅助（Th）细胞极化。许多这样的 提示以及检测和整合的机制仍有待理解。在这个建议中，我们将 询问新兴但支持的假设，即新型调节剂AIMP1驱动的DC表达 Th1细胞免疫的生理传播。该假设基于广泛而严格的数据 证明AIMP1的遗传消融会产生TH1极化的缺陷 比在IL-12或IL-12R缺陷型小鼠中表征的那些。 AIMP1淘汰小鼠失去了安装的能力 针对流感的自适应免疫反应，表现出对正常挑战的完全致命性， 缺乏HA特异性IgG2A产生，以及通过感染后肺中几乎所有分泌IFN-G的T细胞的损失 第15天。AIMP1 - / - 动物也表现出完全失去抗肿瘤免疫力的损失 WildType DC的转移。从机械上讲，数据表明这些缺陷是由于p38mapk激活不足 在AIMP1 - / - DC中，AP-1异二聚化下游失调。 AIMP1与人的直接相关性 疾病是通过泛癌的TCGA生物信息学分析来验证的，对9,000次原发性人类肿瘤Sam- ples，揭示了表达AIMP1水平升高的患者的意外70％的生存优势 原发性肿瘤。在此数据集中，升高的AIMP1表达与活化的直流基因高度相关 签名和Th1免疫轮廓。令人惊讶的是，这种生存优势在患者中没有概括 原发性肿瘤表现出高水平的IL-12a（p35）表达。这些数据表明未被认可 然而，DC表达的AIMP1在自适应Th1治理中的作用不可或缺的作用，并为 这项研究：确认新的调节因子对于诱导Th1的整合和转导至关重要 DC中的信号将改变目前了解Th1免疫信号传导的范式。机制 AIMP1控制细胞免疫将通过完成三个特定目标来确定。在 目的我将定义体内DC子集的AIMP1功能对于传播Th1免疫力至关重要。 在AIM II中，我们将定义AIMP1与直流调节信号级联的界面的方式。目标 iii我们将定义由于DC种群中AIMP1的条件丢失而导致的效应细胞功能的缺陷。在 所有目的，AIMP1缺陷和IL-12缺陷之间的差异将在适当的情况下进行表征。