NOD2 signalling can both positively and negatively regulate Tolllike receptor (TLR) responses. Previous studies have shown that lack of NOD2 signalling (in NOD2 knockout mice) leads to increased peptidoglycan induction of interleukin (IL)-12 via TLR2. Studies in this issue of Gut show that lack of NOD2 signalling (in patients with NOD2 mutations) leads to decreased CpG induction of tumour necrosis factor and IL-8 via TLR9. The first type of abnormality suggests that NOD2 mutations act by enhancing effector T cell function and the second that NOD2 mutations act by impairing regulatory T cell function. We weigh these possibilities.