Mammals coexist with a luxuriant load of bacteria in the lower intestine (up to 10(12) organisms/g of intestinal contents). Although these bacteria do not cause disease if they remain within the intestinal lumen, they contain abundant immunostimulatory molecules that trigger immunopathology if the bacteria penetrate the body in large numbers. The physical barrier consists only of a single epithelial cell layer with overlying mucus, but comparisons between animals kept in germ-free conditions and those colonized with bacteria show that bacteria induce both mucosal B cells and some T cell subsets; these adaptations are assumed to function as an immune barrier against bacterial penetration, but the mechanisms are poorly understood. In mice with normal intestinal flora, but no pathogens, there is a secretory IgA response against bacterial membrane proteins and other cell wall components. Whereas induction of IgA against cholera toxin is highly T help dependent, secretory IgA against commensal bacteria is induced by both T independent and T dependent pathways. When animals are kept in clean conditions and free of pathogens, there is still a profound intestinal secretory IgA response against the commensal intestinal flora. However, T dependent serum IgG responses against commensal bacteria do not occur in immunocompetent animals unless they are deliberately injected intravenously with 10(4) to 10(6) organisms. In other words, unmanipulated pathogen-free mice are systemically ignorant but not tolerant of their commensal flora despite the mucosal immune response to these organisms. In mice that are challenged with intestinal doses of commensal bacteria, small numbers of commensals penetrate the epithelial cell layer and survive within dendritic cells (DC). These commensal-loaded DC induce IgA, but because they are confined within the mucosal immune system by the mesenteric lymph nodes, they do not induce systemic immune responses. In this way the mucosal immune responses to commensals are geographically and functionally separated from systemic immunity.