CagA-dependent Hobit + gastric tissue-resident memory T cells confer full protection from Helicobacter pylori reinfection

Background Helicobacter pylori infection is the most prevalent bacterial infection worldwide. Attempts to develop a vaccine have not been successful, partly due to the absence of well-defined immune correlates of protection. The inflammatory response to H. pylori infection is characterised by the recruitment of T cells expressing markers of tissue-resident memory T (T RM ) cells to the gastric mucosa. However, the function of T RM cells in gastric tissue during H. pylori reinfection remained poorly understood. Objective We aimed to investigate the induction, development and function of gastric T RM cells during primary and secondary H. pylori infection. Design We characterised gastric H. pylori –specific T RM cells in mice and humans by flow cytometry, immunohistochemistry, immunofluorescence, ChipCytometry staining and single-cell RNA sequencing. The function of gastric T RM cells was established in H. pylori eradication and reinfection experiments as well as by targeted depletion of Hobit + T RM cells and neutrophils in mice. Results Expression of the transcription factor Hobit governs the induction and development of gastric T RM cells, which largely depend on the presence of the H. pylori virulence factor Cytotoxin-associated gene A. H. pylori -specific CD4 + and CD8 + T RM cells resided long-term in the stomach and conferred complete protection from reinfection with the help of neutrophils. Gastric CD8 + T RM cells exhibited varying Hobit expression levels and clustered into distinct subgroups based on distinct transcriptomic and cytokine profiles, suggesting functional specialisation. Conclusion These findings establish gastric T RM cells as bona fide correlates of protection against H. pylori , highlighting their potential for future prophylactic and therapeutic strategies.