Figure 1

Organisms such as helminths and environmental saprophytes, which are part of mammalian evolutionary history ("old friends") and must be tolerated, are detected by pattern recognition receptors such as Toll-like receptor 2 (TLR2) and CARD15 (caspase recruitment domain family, member 15) on dendritic cells (DCs). The DCs mature into regulatory DCs that drive regulatory T cell (Treg) responses to the antigens of these organisms. The continuing presence of these antigens in the gut flora, in food, or resident as parasites such as microfilariae leads to continuous background release of regulatory cytokines from these Tregs, exerting bystander suppression of other responses, as shown in the upper arm of the figure. Meanwhile, the increased numbers of regulatory DCs lead to increased processing by such DCs of self-antigens, gut content antigens, and allergens, as shown in the lower arm of the figure. Therefore, the numbers of Tregs specifically triggered by these antigens is also increased, downregulating autoimmunity, inflammatory bowel disease, and allergies, respectively. CTLA-4 = cytotoxic T-lymphocyte antigen 4; IL-10 = interleukin-10; TGF-β = transforming growth factor β.