Immunological tolerance: Danger –  pathogen on the premises!

The March 22 issue of Science carried three articles [1–3] that claim to challenge a key principle of immunology, called self–non-self discrimination, by examining neonatal tolerance. These papers demonstrate that newborn mice can make immune responses if the antigen is appropriately presented. Is this a refutation of self–non-self discrimination as the authors believe? And does it prove the ‘danger theory’ of Polly Matzinger, a leading proponent of this idea and the senior author of the first of the three articles? We shall argue that self–non-self discrimination is alive and well, and that the ‘danger signals’ that alert the immune system are co-stimulatory molecules and cytokines induced by pathogens recognized by the innate immune system.