The role of AIM2 in T cell-mediated autoimmunity

AIM2 在 T 细胞介导的自身免疫中的作用

基本信息

批准号：
10083178
负责人：
Roland M Tisch
金额：
$ 38.88万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-05 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083178
关键词：
AIM2 gene AKT Signaling Pathway Affect Antigen-Presenting Cells Antigens Autoimmune Diseases Autoimmune Process Autoimmunity Automobile Driving Binding CD4 Positive T Lymphocytes Cell Compartmentation Cell Death Cell physiology Cells Cellular immunotherapy Complex DNA DNA-dependent protein kinase Defect Dendritic Cells Development Diabetes Mellitus Eragrostis Event Exhibits Foundations Goals Homeostasis Host Defense Human Hypersensitivity Immune Immunotherapy Inbred NOD Mice Inflammasome Inflammation Insulin-Dependent Diabetes Mellitus Interleukin-18 Malignant Neoplasms Mediating Mediator of activation protein Mind Modeling Natural Immunity PI3K/AKT Pathogenicity Pathway interactions Peripheral Phenotype Phosphorylation Production Property Proto-Oncogene Proteins c-akt Regulation Role Self Tolerance Signal Pathway Signal Transduction Stimulus T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Thymic epithelial cell Thymus Gland Tissues Work base central tolerance diabetogenic ds-DNA immunoregulation insight negative affect novel pathogen pathogenic microbe peripheral tolerance prevent response sensor

项目摘要

SUMMARY/ABSTRACT T cell-mediated autoimmune diseases such as Type 1 diabetes (T1D) are due to complex events leading to dysregulation of central and peripheral tolerance. Defining the mechanisms regulating self-tolerance are critical for understanding the autoimmune process as well as for rational development of immunotherapies to prevent and treat T1D and other T cell-mediated autoimmune diseases. This application is based on our novel observation that NOD mice deficient in the AIM2 inflammasome molecule remain diabetes-free. AIM2 is a cytoplasmic immune sensor involved in host defense. Upon binding double stranded DNA from a microbial pathogen, AIM2 assembles into an inflammasome complex that drives the production of proinflammatory IL-1bβ and IL-18, and pyroptosis-mediated cell death. Recent studies, however, have demonstrated that AIM2 can serve a regulatory function outside of host defense via a nonconical pathway that is independent of inflammasome activation. Here, AIM2 functions as a negative regulator of the kinase DNA-PK in the PI3K/AKT signaling pathway. We find that the lack of diabetes in AIM2-deficient NOD mice is also independent of inflammasome activation. Furthermore, evidence suggests that bβ cell autoimmunity in AIM2-deficient NOD mice is blocked by multiple mechanisms affecting thymic antigen presenting cells, peripheral dendritic cell function and T cell subset differentiation. We hypothesize that AIM2 serves as a key checkpoint in regulating PI3K/DNA-PK/AKT- dependent stimuli and cellular maturation/differentiation, which impacts self-tolerance and the diabetogenic response. Our goal is to define the key mechanisms by which AIM2 regulates self-tolerance. With this in mind, Specific Aim 1 will focus on AIM2 effects on the stimulatory function of medullary thymic epithelial cells and thymic dendritic cells. Specific Aim 2 will define the role of AIM2 in regulating dendritic cell proinflammatory versus tolerogenic function. Finally, Specific Aim 3 will investigate how AIM2 controls the efficiency of pathogenic T cell subset differentiation. This work is expected to provide insight into new mechanisms and pathways by which central and peripheral self-tolerance are regulated, as well as a foundation to target the AIM2 pathway for therapeutic purposes.

摘要/摘要 T 细胞介导的自身免疫性疾病，例如 1 型糖尿病 (T1D)，是由于复杂的事件导致中枢和外周耐受失调的定义至关重要。了解自身免疫过程以及合理开发免疫疗法以预防并治疗 T1D 和其他 T 细胞介导的自身免疫性疾病。该应用基于我们的新观察，即缺乏 AIM2 炎性体的 NOD 小鼠 AIM2 分子保持无糖尿病状态，是一种参与宿主防御的细胞质免疫传感器。来自微生物病原体的双链 DNA，AIM2 组装成炎症小体复合物，驱动促炎性 IL-1bβ 和 IL-18 的产生以及焦亡介导的细胞死亡。然而，已经证明 AIM2 可以通过宿主防御之外的调节功能独立于炎症小体激活的非圆锥通路在此，AIM2 发挥负作用。 PI3K/AKT 信号通路中激酶 DNA-PK 的调节因子。我们发现 AIM2 缺陷型 NOD 小鼠没有患糖尿病也与炎症小体激活无关。此外，有证据表明，AIM2 缺陷型 NOD 小鼠中的 bβ 细胞自身免疫被多种药物阻断。影响胸腺抗原呈递细胞、外周树突状细胞功能和 T 细胞亚群的机制我们认为 AIM2 是调节 PI3K/DNA-PK/AKT- 的关键检查点。依赖性刺激和细胞成熟/分化，影响自我耐受性和糖尿病发生考虑到这一点，我们的目标是定义 AIM2 调节自我耐受的关键机制。具体目标 1 将重点关注 AIM2 对胸腺髓质上皮细胞刺激功能的影响和胸腺树突状细胞。具体目标 2 将定义 AIM2 在调节树突状细胞促炎症中的作用。最后，Specific Aim 3 将研究 AIM2 如何控制效率。这项工作有望提供对新机制和致病性 T 细胞亚群分化的见解。调节中枢和外周自我耐受的途径，以及针对目标的基础用于治疗目的的 AIM2 通路。