Regulation of the immune response--lessons from transgenic models

Generation of the immune antigen receptor repertoire by means of semi-random recombination requires a mechanism for ensuring that self reactivity is constrained. A model is presented which accounts not only for the generation of self tolerance during ontogeny but also for regulation of tolerance and immunity in peripheral immune responses. The model proposes a hierarchy of immune regulation in which antigen presenting cells (APCs) determine the responses of T cells and T cells those of B cells. APCs respond to environmental triggers such as microbes, particulate antigen and tissue injury by becoming highly immunogenic for T cells. At other times, APCs can either be non-stimulatory or tolerogenic, depending on their environment. The model suggests that during ontogeny T and B cells mature in a tolerogenic environment in the thymus and bone marrow, thus ensuring that immunological tolerance results from early contact with self antigen.