# The role of Absent in Melanoma 2 (Aim2) in CD8+ T cell regulation and Helicobacter-induced gastric pathology

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $195,000

## Abstract

PROJECT SUMMARY
While lung cancer holds the top spot for cancer-causing mortality in the US, the combined mortality
attributed to cancers in the digestive diseases, where GI tract cancers account for half of the cases, exceeds
that of lung cancer. Chronic inflammation is a shared risk factor for GI tract cancers, which can lead to the
development of premalignant lesions (e.g., intestinal metaplasia of the esophagus, stomach, and biliary
tract but also colonic dysplasia-associated lesions and mass (DALM) in inflammatory bowel disease (IBD)).
Improved understanding of how chronic inflammation develops by generating new knowledge that more
precisely defines the mechanisms that lead to cellular infiltration in the GI tract is critical as it opens the
door for novel target discovery in treating this condition. In the stomach, the inflammation-intestinal
metaplasia-gastric cancer sequence (a.k.a., Correa cascade) is well-established especially in Helicobacter
pylori infection but there is currently no effective treatment for chronic gastritis particularly when observed
in post-H. pylori eradication or antibiotic refractory H. pylori infection. We proposed a previously
unrecognized mechanism of H. pylori gastritis. Our novel data show that Absent In Melanoma 2 (AIM2),
a part of the inflammasome that contributes to host defense against bacteria and viruses, is a major
regulatory pathway during chronic Helicobacter infection. Because the C-terminal HIN domain of AIM2
binds double-stranded DNA and acts as a cytosolic dsDNA sensor that leads to autoactivation of caspase-
1, an enzyme that processes the proinflammatory cytokine IL-1β, we therefore initially expected AIM2-/-
mice to develop less severe Helicobacter gastric pathology. However, our surprising data show that,
compared to infected wild-type mice, infected AIM2-/- mice had significantly more gastritis characterized by
a significant increase in CD8+ tissue-resident memory T cells (TRM). This suggests that AIM2 ameliorates
gastric pathology via a mechanism that is independent of its known inflammasome function. Our related
work thus far strongly implicates that Helicobacter-induced AIM2 in B cells suppresses the infiltration of
CD8+ TRM by negatively regulating B cell chemokine (CXCL16 and CXCL9) production. Based on our
preliminary data in this proposal, we hypothesize that AIM2 induction in gastric B cells regulates
Helicobacter-associated gastritis by chemokine (CXCL16 and CXCL9)-mediated retention of CD8+ tissue-
resident memory T cell. In this proposal, we will investigate how AIM2 regulates gastric B cell function and
maturation, CD8+ TRM retention, and correlate H. pylori pathology to AIM2 mutations in patients. While
screening for AIM2 genetic variants may help to predict severe H. pylori complications, completion of the
proposed study may also provide novel targets for epithelial inflammation especially conditions that are
mediated by TRM such as IBD.

## Key facts

- **NIH application ID:** 10198725
- **Project number:** 5R21AI154128-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Mohamad El-Zaatari
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $195,000
- **Award type:** 5
- **Project period:** 2020-06-19 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198725

## Citation

> US National Institutes of Health, RePORTER application 10198725, The role of Absent in Melanoma 2 (Aim2) in CD8+ T cell regulation and Helicobacter-induced gastric pathology (5R21AI154128-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10198725. Licensed CC0.

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