Abstract
Helicobacter pylori infects approximately half of the world's population, resulting in lifelong gastric infections. To promote lifelong colonization, H. pylori modulates host immunity via unknown mechanisms. Here we show that H. pylori can harness the pan-immunosuppressive cytokine interleukin-37 (IL-37) to facilitate pathogenesis, enhance colonization and prevent the development of innate, cellular and humoral immunity. We show that H. pylori increased the production of IL-37 in human gastric biopsies, and IL-37 secretion by gastric epithelial cells and human gastric mucosoids. We found that H. pylori induced IL-37 secretion by epithelial cells via activation of host pathogen recognition receptors TLR2, TLR4 and NOD1, in addition to the H. pylori-encoded cag pathogenicity island, revealing that H. pylori utilises multiple mechanisms to induce IL-37 production during infection. Once produced, IL-37 attenuated TLR2, TLR4 and NOD1-mediated activation and TLR-mediated IL-8 responses to H. pylori infection. Using transgenic mice expressing human IL-37, we found that IL-37 promoted immunosuppression by significantly increasing H. pylori colonization, limiting gastric inflammation, and reducing H. pylori-specific antibody responses. Furthermore, we identified the multiple mechanisms whereby IL-37 functions to impair the development of adaptive immunity. IL-37 abolished human T and B cell responses by impairing their activation, migration, and preventing immune synapse formation. Moreover, IL-37 inhibited proliferation of gastric-derived H. pylori-specific T cells isolated from H. pylori-infected patients, revealing a mechanism whereby IL-37 functions to prevent pathogen-specific cellular immune responses. Collectively, our findings reveal that H. pylori induces production of the pan-immunosuppressive cytokine IL-37 to enhance colonization, modulate gastritis and suppress innate, cellular and humoral immunity to ultimately promote pathogenesis in the host. These findings advance our understanding of H. pylori-mediated disease and identify gastric IL-37 as a therapeutic target to combat H. pylori infection and associated diseases.