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

• 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
• 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

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，如1型糖尿病(T1D)，是由于复杂的事件导致的 中枢和外周耐受性失调。确定调节自我容忍的机制至关重要 了解自身免疫过程以及合理开发免疫疗法以预防 治疗T1D和其他T细胞介导的自身免疫性疾病。 这一应用是基于我们新的观察结果，即NOD小鼠缺乏AIM2炎症小体 分子仍未患上糖尿病。AIM2是一种参与宿主防御的细胞质免疫感受器。在绑定时 来自微生物病原体的双链DNA，AIM2组装成一个炎症体复合体，驱动 促炎因子IL-1bβ和IL-18的产生，以及由下垂引起的细胞死亡。最近的研究表明， 然而，AIM2已经证明了AIM2可以通过一个 不依赖于炎性小体激活的非锥形通路。在这里，AIM2起否定的作用 PI3K/AKT信号通路中的激酶DNA--PK调节因子。 我们发现，AIM2缺陷的NOD小鼠中糖尿病的缺乏也独立于炎症体的激活。 此外，有证据表明，在aim2基因缺陷的NOD小鼠中，bβ细胞的自身免疫被多个 胸腺抗原提呈细胞、外周血树突状细胞功能及T细胞亚群的影响机制 差异化。我们假设AIM2是调控PI3K/DNA-PK/AKT-的关键检查点。 依赖刺激和细胞成熟/分化影响自身耐受性和糖尿病的发生 回应。我们的目标是定义AIM2调节自我耐受的关键机制。考虑到这一点， 具体目标1将集中在AIM2对延髓胸腺上皮细胞刺激功能的影响和 胸腺树突状细胞。特异性目标2将确定AIM2在调节树突状细胞致炎中的作用 而不是耐受性功能。最后，《特定目标3》将调查AIM2如何控制 致病T细胞亚群分化。这项工作有望为深入了解新的机制和 调节中枢和外周自我耐受的途径，以及靶向 用于治疗目的的AIM2途径。