The stomach pathogen, Helicobacter pylori causes chronic inflammation, characterised by the recruitment and activation of immune cells, including macrophages, dendritic cells and lymphocytes. Nevertheless, less than 1% of H. pylori-infected individuals develop severe forms of disease, including gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. The diversity of clinical outcomes from H. pylori infection highlight the likely importance of host factors in disease progression. Despite extensive research on the pathogenesis of H. pylori infection, however, many aspects of bacterial-host interactions in this infection remain to be elucidated. Recent studies in the laboratory have identified a mechanism by which H. pylori is able to modulate pro-inflammatory responses in macrophages. Specifically, we have found that H. pylori targets a member of the NOD-like receptor (NLR) family of pattern recognition receptors. This newly discovered NLR member, the NOD-like receptor family CARD domain containing 5 (NLRC5) protein, has been reported to act as a regulator of pro-inflammatory responses in macrophages. We demonstrated upregulation of NLRC5 expression in H. pylori-infected human and mouse gastric biopsies, as well as in response to Helicobacter stimulation in primary and immortalised macrophages. Moreover, our data suggests that NLRC5 regulates pro-inflammatory cytokine induction, and the production of factors that drive B cell proliferation in response to Helicobacter infection. Consistent with this finding, mice that lack myeloid cell-specific Nlrc5 exhibit a more rapid and pronounced development of gastric lymphoid tissue formation, similar to the precursor lesions of B cell MALT lymphoma, in response to Helicobacter infection. We propose that macrophage-derived NLRC5 may act as a regulator of pro-inflammatory responses and that aberrant NLRC5 signalling may be a factor in the development of H. pylori-associated disease. Collectively, our results indicate that NLRC5 acts to shape the innate and adaptive immune responses during chronic Helicobacter infection to dampen inflammation and gastric MALT formation in the host.