Self-nonself discrimination and tolerance in T and B lymphocytes

J. F. A. P. Miller

The immune system must not only fight off infections, but also ensure that it does not react against its own body tissues. Since clones of lymphocytes have predetermined reactivities, some will be self-reactive and have the potential to cause damage. They should therefore be neutralized in some way. In a system as complex and important as that governing self-tolerance, many mechanisms must exist to neutralize autoaggressive lymphocytes. They may be classified under two main groups. In one the tolerant state arises from the physical or functional silencing of potentially autoaggressive lymphocytes after antigen encounter. This may involve clonal deletion, clonal abortion or clonal anergy. In the second, regulatory mechanisms of the immune system itself may hold autoreactive lymphocytes in check, for example through the operation of idiotypic network interactions and the action of specialized suppressor cells. Much evidence has accumulated for the physical deletion of autoreactive T cells as they mature in the thymus. The fate of any that escape thymus censorship has been the subject of recent research and is discussed here. Under certain conditions, self-tolerance must also be imposed at the B-cell level to prevent the production of potentially damaging autoantibodies. Although the mechanisms which silence self-reactive lymphocytes are very efficient, self-tolerance can break down, and autoimmunity will thus ensue. The main factors responsible for this are briefly described here.