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Innate mechanisms of regulation of Th17 responses

Th17 反应调节的先天机制

基本信息

批准号：
10545742
负责人：
Chandrashekhar Pasare
金额：
$ 47.7万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10545742
关键词：
Adaptive Immune System Autoimmune Autoimmune Diseases Autoimmunity Automobile Driving B-Lymphocytes Bacteria Bypass CASP8 gene CD4 Positive T Lymphocytes Cell Communication Cell Lineage Cells Clinical Treatment Clonal Expansion Code Cues DNA Damage Data Dendritic Cells Disease Event Gene Expression Profile Generations Genes IL1R1 gene Infection Inflammasome Inflammation Inflammatory Inflammatory Response Innate Immune System Instruction Interferons Intestines Invaded Investigation Joints Kidney Ligands Lymphoid Tissue Macrophage Memory Molecular Morbidity - disease rate Mutation Myeloid Cells Natural Immunity Nature Nuclear Organ Outcome Pancreas Pathologic Pathology Pathway interactions Pattern recognition receptor Peptide/MHC Complex Peptides Play Population Process Production Receptor Activation Regulation Role Signal Transduction Skin Stimulator of Interferon Genes Surface Syndrome T memory cell T-Cell Activation T-Lymphocyte TNF gene TNFRSF5 gene Tissues Toxin Tumor Necrosis Factor Receptor Up-Regulation Uric Acid Virus Work adaptive immunity arm ataxia telangiectasia mutated protein autoimmune inflammation autoinflammatory diseases autoreactive T cell autoreactivity chemokine cytokine cytokine release syndrome effector T cell fungus in vivo insight member memory CD4 T lymphocyte microbial mortality novel pathogen programs receptor response secondary lymphoid organ sensor targeted treatment terminally differentiated effector memory (TEM) T cells transmission process

项目摘要

Project Summary/Abstract Induction of inflammation by canonical microbial ligands by engaging classical patten recognition receptors (PRR) has many beneficial outcomes including elimination of the pathogen and activation of adaptive immunity that serves as protection against reinfection. However, unwarranted inflammation can also be induced by aberrant activation of PRRs by noxious agents (toxins, uric acid etc) or because of naturally occurring mutations in sensors or adapters of the innate immune system leading to auto-inflammatory diseases such as Cryopyrin Associated Inflammatory Syndromes, and Interferonopathies. Auto-immune diseases on the other hand are different than auto-inflammatory diseases as the culprits that trigger pathology are self-reactive T and B cells. Auto-immune inflammation can lead to debilitating outcomes because of damage to vital organs such as kidney, pancreas intestines as well as Skin and joints. Paradoxically, many of the clinical treatments for T cell auto-immune diseases are all directed towards inflammatory cytokines made by the innate immune system. Our previous work demonstrated that effector and effector memory CD4 T cells have the capacity to drive IL-1b production, completely independent of pattern recognition receptor activation. We discovered that Effector CD4 T cells provide both signal 1 (TNFa) and signal 2 (FasL) to instruct the myeloid cells to produce IL-1b in a Caspase-8 dependent manner. The current proposal is based on very strong preliminary data that demonstrates that effector CD4 T cells in fact have the capacity to mimic microbial ligands to drive a broad pro-inflammatory program in cells of the innate immune system. We find that effector memory CD4 T cells induce additional genes in Dendritic cells that sets up important questions related to “T cell instruction” of the innate immune system. Here we posit that while proximal activation of PRRs is necessary for naïve T cell activation, effector memory T cells have the ability to directly activate the innate immune system thus bypassing the need for PRR sensing. Although this might have evolved as a beneficial arm of the innate adaptive cross-talk, we propose to understand the detrimental outcomes of adaptive instruction of innate immunity in driving inflammation and tissue pathology. In order to gain mechanistic understanding of innate inflammation driven by effector CD4 T cells, we propose three aims where 1. We will examine and characterize the nature of innate inflammation driven by different effector memory T cell lineages and identify the molecular players involved in this process, 2. We will investigate the molecular mechanisms by which effector memory CD4 T cells drive innate inflammation with a particular focus on STING and DNA damage and 3. We will examine the impact of CD4 T cell effector/effector memory CD4 T cell driven innate inflammation on auto-immune disease and pathology. Successful completion of these aims will provide novel insights into T cell driven innate inflammation independent and will open up new targets to treat auto-immune diseases.

项目概要/摘要经典微生物配体通过结合经典模式识别受体诱导炎症 (PRR) 具有许多有益的结果，包括消除病原体和激活适应性免疫力可防止再次感染。然而，不必要的炎症也可能是由有毒物质（毒素、尿酸等）引起的 PRR 异常激活或自然原因引起先天免疫系统的传感器或适配器发生突变，导致自身炎症疾病，例如冷热蛋白相关炎症综合征和干扰素病。自身免疫另一方面，疾病与自身炎症性疾病不同，因为它们是引发炎症的罪魁祸首。病理学是自身反应性T细胞和B细胞。自身免疫炎症可能导致衰弱的结果因为肾脏、胰腺、肠道以及皮肤和关节等重要器官受损。矛盾的是，许多T细胞自身免疫性疾病的临床治疗都是针对先天免疫系统产生的炎症细胞因子。我们之前的工作证明了效应器效应记忆 CD4 T 细胞有能力驱动 IL-1b 的产生，完全独立于模式识别受体激活。我们发现效应 CD4 T 细胞提供两种信号 1 (TNFa) 和信号 2 (FasL) 指导骨髓细胞在 Caspase-8 依赖性细胞中产生 IL-1b 方式。目前的提案基于非常有力的初步数据，表明效应子 CD4 事实上，T 细胞有能力模仿微生物配体，在体内驱动广泛的促炎症程序。先天免疫系统的细胞。我们发现效应记忆 CD4 T 细胞在树突状细胞提出了与先天免疫系统的“T 细胞指令”相关的重要问题。在这里，我们假设虽然 PRR 的近端激活对于初始 T 细胞激活是必要的，但效应器记忆T细胞有能力直接激活先天免疫系统，从而绕过了对免疫系统的需要。 PRR 传感。尽管这可能已经进化为先天适应性串扰的有益武器，但我们提议了解驾驶中先天免疫的适应性指导的有害结果炎症和组织病理学。为了获得对先天性炎症驱动的机制的理解通过效应 CD4 T 细胞，我们提出了三个目标，其中 1. 我们将检查并表征由不同效应记忆 T 细胞谱系驱动的先天性炎症并确定分子参与者参与这个过程，2.我们将研究效应记忆CD4 T的分子机制细胞驱动先天炎症，特别关注 STING 和 DNA 损伤，3.我们将检查 CD4 T 细胞效应/效应记忆 CD4 T 细胞驱动的先天炎症对自身免疫的影响疾病和病理学。成功完成这些目标将为 T 细胞驱动提供新的见解独立于先天性炎症，并将开辟治疗自身免疫性疾病的新靶点。