Sophie Bukrey
Research Mentor: Mohamad El Zaatari
Mentor Department: Division of Gastroenterology, Department of Internal Medicine, Medicine
Author(s): Sophie Bukrey, Mohamad El Zaatari
Session: Session 7 (4:00 PM – 4:50 PM)
Presentation Type: Poster 38
Abstract
Gastric cancer develops through a multistep process driven by chronic inflammation,
most commonly initiated by persistent Helicobacter pylori (H. pylori) infection. Prolonged infection promotes immune cell infiltration, tissue damage, and the emergence of preneoplastic lesions such as spasmolytic peptide-expressing metaplasia (SPEM), which can progress toward malignancy. Although CD8+ T cells contribute to gastric inflammation during H. pylori infection, the molecular mechanisms regulating their function in this setting remain unknown. Absent in melanoma 2 (AIM2) is best characterized for its role in inflammasome signaling, where it mediates innate immune responses through cytosolic DNA sensing and caspase-1 activation. However, our preliminary mouse studies suggest that AIM2 also plays a regulatory role in adaptive immunity during gastric disease, as its deficiency leads to increased CD8+ T-cell infiltration and the exacerbation of Helicobacter-induced gastric metaplastic lesions. Further evidence from lymphocyte-deficient mice reconstituted with AIM2-deficient CD8+ T cells supports a CD8+ T cell-intrinsic role for AIM2 in limiting gastric inflammation and metaplasia. The objective of this project is to define the molecular mechanisms by which CD8+ T cell-intrinsic AIM2 regulates CD8+ T cell function during the progression of gastric disease. To achieve this, AIM2-FLAG constructs driven by either the CD8a promoter, to enable CD8+ T cell-specific overexpression, or the AIM2 promoter, to approximate physiological expression, are being generated. These systems will be used to identify AIM2-associated protein complexes through immunoprecipitation. Functional consequences of AIM2 expression will be assessed using co-culture assays in which CD8+ T cells are primed by H. pylori-pulsed bone marrow-derived dendritic cells to examine activation, differentiation, and effector responses. Immunofluorescence analyses of gastric tissue will be used to localize AIM2 and associated signaling components. Overall, these studies aim to define how AIM2 regulates CD8+ T cell behavior during chronic gastric inflammation, providing mechanistic insight that may inform future immunotherapeutic strategies targeting CD8+ T cell function in chronic inflammatory disease and cancer.
