Infection is a major risk factor for cancer. The bacterium, Helicobacter pylori, is a leading cause of infection-related cancer and has become a model for understanding the role of infectious agents in tumorigenesis. H. pylori infection is highly associated with a form of B cell lymphoma affecting the stomach, known as mucosa-associated lymphoid tissue (MALT) lymphoma. Antibiotic therapies are effective in treating these lymphomas, but only in early-stage disease and not in all cases. The relative rarity and indolence of gastric MALT lymphoma has impeded an understanding of its pathogenesis and the development of new treatments. We have generated a mouse model in which animals develop gastric MALT at 3 months post-Helicobacter infection versus 9-24 months in existing models. These mice have a myeloid-specific deletion of the innate immune molecule, Nlrc5. MALT lesions in Nlrc5 knockout (KO) mice reproduce the key histopathological features of the human disease. We showed that Nlrc5 plays a protective role against the development of B cell MALT lymphoma and identified B cell-activating factor (BAFF), produced by macrophages, as being a key driver of B cell proliferation in this model. In therapeutic studies, the blockade of BAFF signalling was able to both prevent and reduce B cell MALT formation. RNA-sequencing showed that the macrophages from Nlrc5 KO mice have a gene expression profile similar to that of tumour-associated macrophages (TAMs), a cell population with immunosuppressive and pro-tumorigenic functions. We propose that the findings from this research may be relevant to an understanding of other forms of B cell lymphoma for which both the incidence and links with various types of infection are increasing.