The historical postulate is not the basis of self-nonself discrimination: A response to Bretscher's proposal.

Peter Bretscher was the first to envision that the problem of self-nonself discrimination in the adaptive immune system could be solved by positing that antigen inactivates single lymphocytes, whereas antigen-mediated lymphocyte cooperation is required to stimulate their activation. These ideas led to a two-signal model for lymphocyte activation: an antigen-specific signal that when generated alone results in tolerance and the combination of two (or more) antigen-specific signals resulting in lymphocyte activation and immunity. This 'quorum model' is consistent with the concept known as the historical postulate that posits that the early life timing of antigen exposure is the key to self-tolerance. Bretscher proposes that the historical postulate is 'the basis, at level of the system, for self-nonself discrimination' and contends that the Danger model violates this postulate. Herein I argue that the data do not support putting the historical postulate alone at the top of the hierarchy of concepts underlying self-nonself discrimination. The location of antigen is at least as important because it determines whether central tolerance will be engaged. Location of antigen together with timing of antigen exposure are major factors determining whether quorum, the basis for self-nonself discrimination, is achieved.