<i>Helicobacter pylori</i> induces the production of interleukin-37 to promote broad immunosuppression and enhance colonization

<i>Helicobacter pylori</i> infects approximately half of the world's population, resulting in lifelong gastric infections. To promote lifelong colonization, <i>H.</i> <i>pylori</i> modulates host immunity via unknown mechanisms. Here we show that <i>H.</i> <i>pylori</i> 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 <i>H.</i> <i>pylori</i> 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 <i>H.</i> <i>pylori</i> induced IL-37 secretion by epithelial cells via activation of host pathogen recognition receptors TLR2, TLR4 and NOD1, in addition to the <i>H.</i> <i>pylori</i>-encoded cag pathogenicity island, revealing that <i>H.</i> <i>pylori</i> 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 <i>H.</i> <i>pylori</i> infection. Using transgenic mice expressing human IL-37, we found that IL-37 promoted immunosuppression by significantly increasing <i>H.</i> <i>pylori</i> colonization, limiting gastric inflammation, and reducing <i>H.</i> <i>pylori</i>-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 <i>H.</i> <i>pylori</i>-specific T cells isolated from <i>H.</i> <i>pylori</i>-infected patients, revealing a mechanism whereby IL-37 functions to prevent pathogen-specific cellular immune responses. Collectively, our findings reveal that <i>H.</i> <i>pylori</i> 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 <i>H.</i> <i>pylori</i>-mediated disease and identify gastric IL-37 as a therapeutic target to combat <i>H.</i> <i>pylori</i> infection and associated diseases.