Nature versus nurture: contributions of developmental programming and the microenvironment to B cell tolerance

The original Burnet Lederberg and Bretscher Cohn models of immunological tolerance are essentially incompatible, one considering tolerance to be the obligatory outcome of antigen recognition by an immature lymphocyte and the other considering it as one of two possible responses to antigen, the crucial determinant being interaction with a second antigen-reactive cell. The early experimental evidence was confusing, in that it appeared to support both theories. In response to this situation, a hybrid model retaining some of the features of the original models was proposed. In particular, immature B cells were regarded as 'hypersensitive to tolerance induction', but could also make a positive response to antigen under some circumstances. More recent data from B cell transgenic mice have challenged even these hybrid models, stimulating renewed interest in the question of how B cell tolerance is regulated in vivo. This article presents a new interpretation of the data, in which the increased resistance of mature B cells to tolerance induction is postulated to result from partial receptor desensitization in response to environmental antigen, rather than from a developmentally programmed change in B cell signalling. Thus, it is suggested that Burnet's 'window of tolerance induction' is determined by the environment rather than developmental pre-programming. If this postulate is accepted, induction of B cell self-tolerance in both the bone marrow and periphery follows the simple and elegant rules originally laid down by Bretscher and Cohn.