1261

REGULATION OF INTRAEPITHELIAL CD8+ T CELL INTERACTION WITH EPITHELIAL MHC-I BY ABSENT IN MELANOMA 2 IN GASTRIC PRE-NEOPLASTIC LESIONS.

Date
May 21, 2024

Background: Novel and recent discoveries have shown that antigen presentation to gut T cells can be carried out by gut epithelial cells in the colon. Here we show, in the inflamed stomach, that gastric epithelial cells highly express MHC-I and interact with intraepithelial CD8+ T cells, and that Absent in Melanoma 2 (Aim2) can regulate the frequency of intraepithelial CD8+ T cells. Understanding this mechanism and modulating CD8+ T cell education by gastric epithelial MHC-I can be useful in regulating the outcome of gastric pre-neoplastic and neoplastic lesions. Methods: We used a combination of methods including (1) immunofluorescence of intraepithelial E-cadherin+ CD8+ T cells in tissue sections from human gastric biopsies, (2) single-cell RNA sequencing (scRNA-Seq) of WT vs Aim2-/- 6-month H. felis-infected stomachs, (3) WT → Aim2-/- vs Aim2-/- → WT bone marrow chimeras, (3) CD19CreAim2flox/flox vs Aim2flox/flox mice, and (4) H. pylori-pulsed BMDC:T cell co-culture of WT vs Aim2-/- splenocytes. Results: Intraepithelial CD8+ T cells, which also expressed E-cadherin, were identified, by immunofluorescence, in biopsies from subjects with chronically inflamed gastric mucosae due to chronic H. pylori infection. The cell membranes of these cells were in contact with β2 microglobulin (MHC-I subunit) expressed by gastric mucous pit and neck cell membranes. In mice, MHC-I was similarly induced in gastric epithelial cells by 6-month H. felis or H. pylori infection, relative to uninfected. Intraepithelial CD8+ T cells were identified by scRNA-Seq, and they clustered with gastric epithelial cells rather than the T cell cluster, as they co-expressed a combination of CD8+ T cell and epithelial cell markers. scRNA-Seq showed that Aim2 was downregulated in these hybrid intraepithelial CD8+ T cells, relative to stromal E-cadherin- CD8+ T cells. To determine which compartment Aim2 exerts its impact on CD8+ T cells, we performed bone marrow chimera experiments (e.g., Aim2-/- → WT vs WT → Aim2-/-) followed by 6mo H. felis infection, and observed an increase in intraepithelial CD8+ T cells in Aim2-/- → WT but not WT → Aim2-/-, thus implicating a non-epithelial-intrinsic Aim2 effect. Moreover, CD19CreAim2flox/flox followed by 6mo H. felis also failed to recapitulate the Aim2 phenotype, thereby excluding B cell-intrinsic Aim2 involvement. Myeloid Aim2 involvement was also ruled out in a previous report. In contrast, CD8+ T cell-intrinsic Aim2 deficiency increased the expression of IFN-γ and tissue-resident memory T cell markers CD69 and CD103 in H. pylori-pulsed BMDC:T cell ex-vivo co-culture experiments. Conclusion: Our study suggests that intraepithelial engagement of gastric CD8+ T cells with epithelial cells may lead to downregulation of CD8 T cell Aim2 expression, thereby increasing pathogenic CD8 T cell phenotype.

Tracks

Related Products

Thumbnail for PANEL DISCUSSION
PANEL DISCUSSION
40 years after the organism was first recognized and grown in culture, Helicobacter pylori infections are still commonly encountered in practice,. This symposium will focus on several areas that remain unresolved to this day - including how best to manage H…
Thumbnail for ENHANCED EFFICACY OF COMBINED BISMUTH AND HIGH-DOSE DUAL THERAPY COMPARED TO HIGH-DOSE DUAL THERAPY ALONE OR QUADRUPLE THERAPY FOR FIRST-LINE HELICOBACTER PYLORI ERADICATION – AN INTERIM REPORT OF A MULTI-CENTER, RANDOMIZED CONTROLLED STUDY
ENHANCED EFFICACY OF COMBINED BISMUTH AND HIGH-DOSE DUAL THERAPY COMPARED TO HIGH-DOSE DUAL THERAPY ALONE OR QUADRUPLE THERAPY FOR FIRST-LINE HELICOBACTER PYLORI ERADICATION – AN INTERIM REPORT OF A MULTI-CENTER, RANDOMIZED CONTROLLED STUDY
BACKGROUND: Tools predicting incident esophageal adenocarcinoma (EAC) and gastric cardia adenocarcinoma (GCA) that can be automated in electronic health records (EHRs) to guide screening decisions are needed…
Thumbnail for AGA Best of DDW in Chinese
AGA Best of DDW in Chinese
This session brings Chinese speaking experts together to provide a broad overview highlighting the best of AGA programming at Digestive Disease Week® (DDW) 2023 for Chinese speaking audiences…
Thumbnail for ADVERSE EFFECTS OF H. PYLORI TREATMENTS: THE OBVIOUS AND THE OCCULT
ADVERSE EFFECTS OF H. PYLORI TREATMENTS: THE OBVIOUS AND THE OCCULT
40 years after the organism was first recognized and grown in culture, Helicobacter pylori infections are still commonly encountered in practice,. This symposium will focus on several areas that remain unresolved to this day - including how best to manage H…