An asymptomatic infection may play a role in facilitating celiac disease, a new study in mice reveals. The study highlights a previously unexplored connection between viral infection and oral tolerance to dietary antigens, showing how viruses can break this tolerance, which is otherwise needed to prevent undesirable responses to innocuous antigens ingested with food. Celiac disease, an autoimmune disorder where the ingestion of gluten leads to damage in the small intestine, has been thought to be primarily a genetic disease. Although epidemiological evidence has linked viral infections with the initiation of Celiac disease, experimental evidence of this connection is lacking. To gain more insights into this relationship, Romain Bouziat et al. studied the effects of two different reovirus strains that infect humans, type 1 Lang (T1L) and type 3 Dearing (T3D). The two viruses differ in pathogenesis, whereas T1L infects the intestine, perturbing regular immune functioning, T3D does not naturally infect the intestine. The researchers engineered a strain of T3D that is capable of infecting the intestines of mice and compared the effects of doing so to infection with T1L. They found that both viruses evoked protective immune responses, yet T1L evoked a more virulent response if the infection was caused in the presence of a dietary antibody, such as gluten or ovalbumin. Further exploration revealed that, upon exposure to T1L, antigen-presenting dendritic cells mounted a pathogenic T-cell response, one dependent on Interferon regulatory factor 1 (IRF1), which, coincidently, has been found at higher levels in the mucosa of children with celiac disease. The results are highlighted in a Perspective by Elena F. Verdu and Alberto Caminero.