The role of AIM2 in T cell-mediated autoimmunity

总结/摘要 T细胞介导的自身免疫性疾病如1型糖尿病（T1 D）是由于复杂的事件导致的， 中枢和外周耐受性失调。确定调节自我耐受性的机制至关重要 了解自身免疫过程以及合理开发免疫疗法以预防 并治疗T1 D和其他T细胞介导的自身免疫性疾病。 本申请基于我们的新观察，即AIM 2炎性小体缺陷的NOD小鼠 分子保持无糖尿病。AIM 2是一种参与宿主防御的细胞质免疫传感器。结合后 AIM 2是一种来自微生物病原体的双链DNA，它组装成一种炎性复合体， 促炎性细胞因子IL-1bβ和IL-18的产生，以及细胞凋亡介导的细胞死亡。最近的研究， 然而，已经证明AIM 2可以在宿主防御之外通过免疫调节来发挥调节功能。 非锥形途径，独立于炎性小体激活。在这里，AIM 2起着消极的作用。 PI 3 K/AKT信号通路中的激酶DNA-MAPK的调节剂。 我们发现，AIM 2-β 1缺陷型NOD小鼠中糖尿病的缺乏也独立于炎性小体激活。 此外，有证据表明，在AIM 2-β 1缺陷NOD小鼠中，Bβ细胞自身免疫被多种免疫抑制剂阻断。 胸腺抗原呈递细胞、外周树突状细胞功能和T细胞亚群的影响机制 分化我们推测AIM 2在调节PI 3 K/DNA-PKK/AKT-PKK过程中起着关键的检查点作用 依赖性刺激和细胞成熟/分化，其影响自身免疫耐受和糖尿病发生。 反应我们的目标是确定AIM 2调节自我耐受性的关键机制。考虑到这一点， 具体目标1将侧重于AIM 2对胸腺髓质上皮细胞刺激功能的影响， 胸腺树突状细胞。特异性Aim 2将定义AIM 2在调节树突状细胞促炎中的作用 与致耐受性功能相比。最后，具体目标3将研究AIM 2如何控制 致病性T细胞亚群分化。预计这项工作将有助于深入了解新的机制， 调节中枢和外周自我耐受的途径，以及靶向 AIM 2通路用于治疗目的。

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.