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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

基本信息

批准号：
10397673
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
项目类别：
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/10397673
关键词：
Ablation Adoptive Transfer Alleles Animals Antitumor Response Attenuated Vaccines Autoimmune Diseases Back Binding Bioinformatics Biological Blocking Antibodies Blood Circulation Bone Marrow Cell physiology Cells Cellular Immunity Clinical Communicable Diseases Complex Cues DUSP1 gene Data Data Set 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 Pharmacology 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 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 Virus Virus Diseases Work adaptive immune response anti-tumor immune response antiviral immunity arm base cancer therapy cell type cytokine dimer 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 pathogen polarized cell response transcriptome sequencing tumor vaccination strategy

项目摘要

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.

抽象的在活病毒疫苗接种之外仍然无法产生有效的细胞介导的免疫力对于免疫功能低下个体的疫苗接种来说，细胞介导的预防是一个普遍的临床问题尚无活疫苗的病毒性疾病，最重要的是，产生持久的抗肿瘤免疫回应。细胞介导的免疫由树突状细胞 (DC) 启动，树突状细胞是先天免疫的关键谱系，作为先天性和适应性免疫臂之间的主要接触点和串扰系统。成功应对病原体需要 DC 检测并整合广泛的环境因素精确控制关键下游反应的线索，特别是辅助 T 细胞 (TH) 细胞极化。很多这样的线索以及检测和整合机制仍有待了解。在本提案中，我们将质疑新兴但得到充分支持的假设，即新型调节器 AIMp1 的 DC 表达驱动 TH1 细胞免疫的生理传播。这个假设是基于广泛而严格的数据证明 AIMp1 的基因消融会导致 TH1 极化的缺陷明显更加严重与 IL-12 或 IL-12R 缺陷小鼠中的特征相比。 AIMp1 敲除小鼠失去了安装的能力针对流感的适应性免疫反应，对通常的亚致死攻击表现出完全致死性， HA 特异性 IgG2a 产生不足，感染后肺部几乎所有分泌 IFN-g 的 T 细胞丧失第 15 天。AIMp1-/- 动物也表现出抗肿瘤免疫力完全丧失，可以通过收养来挽救野生型DC的转移。从机制上讲，数据表明这些缺陷是由于 p38MAPK 激活缺陷造成的在 AIMp1-/- DC 中，AP-1 异二聚化下游失调。 AIMp1 与人类的直接相关性该疾病通过对 9,000 个原发性人类肿瘤样本的泛癌 TCGA 生物信息学分析得到验证例如，揭示了在表达升高的 AIMp1 水平的患者中出人意料的 70% 的生存优势原发肿瘤。在此数据集中，AIMp1 表达升高与激活的 DC 基因高度相关特征和 TH1 免疫特征。引人注目的是，这种生存优势并没有在以下患者中重现：其中原发肿瘤表现出高水平的 IL-12A (p35) 表达。这些数据表明了一个未被认识到的 DC 表达的 AIMp1 在适应性 TH1 治理中发挥着不可或缺的作用，并为这项研究：证实一种新的调节因子对于 TH1 诱导的整合和转导至关重要 DC 中的信号将改变目前对 TH1 免疫信号传导的理解范式。机制 AIMp1通过何种方式控制细胞免疫将由三个具体目标的完成来决定。在目标 I 我们将定义 AIMp1 功能对于 TH1 免疫传播至关重要的体内 DC 子集。在目标 II 中，我们将定义 AIMp1 与 DC 调节信号级联的接口方式。瞄准目标 III 我们将定义 DC 群体中 AIMp1 条件性缺失导致的效应细胞功能缺陷。在所有目标中，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。