Contribution of CagA-specific CD8+ T cell clones to immunity against H. pylori

• Applicant: Professor Dr. Markus Gerhard
• Subject Area: Immunology ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 556014269

Infection with Helicobacter pylori causes chronic gastritis in large parts of the global population. This disease is responsible for 90% of the >1 million gastric cancer cases, which makes H. pylori the leading bacterial cause for cancer-related deaths worldwide. The carcinogenic potential of H. pylori is mainly determined by the virulence factor cytotoxic associated gene A (CagA), which is injected into epithelial cells where it activates several oncogenic signaling pathways. Cytotoxic CD8+ T cells are important in fighting and controlling intracellular pathogens and cancer but have not been considered in the infection with the extracellular bacterium H. pylori. We have recently shown that CagA-specific CD8+ T cells play a major role in controlling H. pylori during the early infection phase in mice, and our preliminary data confirms CagA-specific CD8+ T cell responses human. That cytotoxic T cells control an extracellular infectious disease by detecting epitopes derived from a to intracellular translocated oncogenic protein is a novel concept in CD8+ T cell immunity. In the proposed work programme, we seek to precisely describe the mechanisms of how the T cell receptors (TCRs) of CD8+ T cells recognize CagA-derived epitopes on CagA infected cells, and evaluate their therapeutic potential in fighting H. pylori infection and preventing gastric cancer development. We aim to integrate investigations on both humans and mice equally to maintain the clinical significance and perform interventional experiments that are only possible in animal models. Our applied methods include high-performance multicolor flow cytometry, ChipCytometry and single cell RNA-sequencing. First, we want to define the CD8+ T cell epitopes within the CagA protein presented on MHC-I molecules of epithelial cells that elicit CD8+ T cell responses, and also identify and characterize the TCRs recognizing these peptides. With this information, we will be able to investigate CagA-specific CD8+ T cell responses on a single cell level in mice and human. This will provide better understanding of how circulating antigen specific T cells are recruited to the stomach and differentiate into tissue-resident memory T cells in the H. pylori context and for mucosal tissues in general. Further, we will ask if CagA-specific CD8+ T cells are able to eliminate CagA-infected epithelial cells and whether this contributes to bacterial control. If elimination of CagA-infected epithelial cells can be confirmed, we hope to exploit this in future as a novel therapeutic approach to prevent H. pylori infection and gastric cancer development.

• DFG Programme: Research Grants