CagA-dependent Hobit⁺ gastric tissue-resident memory T cells confer full protection from <i>Helicobacter pylori</i> reinfection.

Abstract

<i>Helicobacter pylori</i> 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 <i>H. pylori</i> 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 <i>H. pylori</i> reinfection remained poorly understood. We aimed to investigate the induction, development and function of gastric T_RM cells during primary and secondary <i>H. pylori</i> infection. We characterised gastric <i>H. pylori</i>-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 <i>H. pylori</i> eradication and reinfection experiments as well as by targeted depletion of Hobit⁺ T_RM cells and neutrophils in mice. Expression of the transcription factor Hobit governs the induction and development of gastric T_RM cells, which largely depend on the presence of the <i>H. pylori</i> virulence factor Cytotoxin-associated gene A. <i>H. pylori</i>-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. These findings establish gastric T_RM cells as bona fide correlates of protection against <i>H. pylori</i>, highlighting their potential for future prophylactic and therapeutic strategies.