The role of AIM2 in T cell-mediated autoimmunity

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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.