# The role of AIM2 in T cell-mediated autoimmunity

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2021 · $388,750

## Abstract

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.

## Key facts

- **NIH application ID:** 10083178
- **Project number:** 5R01AI141631-03
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Roland M Tisch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2019-01-05 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083178

## Citation

> US National Institutes of Health, RePORTER application 10083178, The role of AIM2 in T cell-mediated autoimmunity (5R01AI141631-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10083178. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*