Fig. 1.

The immune system requires ‘educational’ input. The microbiota of others, organisms from the natural environment and other tolerated organisms (such as helminths) with which we co-evolved are required to expand the effector and regulatory branches of the immune system. During subsequent encounters with pathogens, danger signals generated by tissue damage enhance effector mechanisms and attenuate regulatory pathways to permit an appropriate immune response. Adequate background levels of regulatory T cells and dendritic cells and other regulatory mechanisms are required to maintain suppression of responses to ‘forbidden targets’ and to switch off inflammation completely when the danger is eliminated, so that proinflammatory mediators do not continue to circulate.