The TNF receptor superfamily member death receptor 3 (DR3) exacerbates Th2- and Th17-cell-mediated inflammatory and autoimmune conditions, yet no role in host defence has been reported. Here, we examined the role of DR3 during infection with Salmonella enterica serovar Typhimurium. Infection resulted in protracted expression of the DR3 ligand TL1A but not the related TNF superfamily proteins OX40L or CD30L. TL1A expression was localized to splenic F4/80+ macrophages where S. enterica Typhimurium replicates, and temporally coincided with the onset of CD4+-cell expansion. To address the relevance of the TL1A-DR3 interaction, we examined immune responses to S. enterica Typhimurium in mice lacking DR3. Infected DR3-/- mice harboured reduced numbers of antigen-experienced and proliferating CD4+ T cells compared with WT mice. Furthermore, the frequency of IFN-γ+ CD4+ T cells in DR3-/- mice was lower throughout the time of bacterial clearance. Importantly, bacterial clearance, which is dependent on Th1 cells, was also impaired in DR3-/- mice. This defect was intrinsic to CD4+ T cells as evidenced by an increase in bacterial burden in RAG2-deficient mice receiving DR3-/- CD4+ T cells compared with WT CD4+-cell recipients. These data establish for the first time a role for DR3 in a host defence responce.