A model for developmentally acquired thymus-dependent tolerance to central and peripheral antigens.

Current models of tolerance to peripheral, tissue-specific antigens contain some major caveats. First, they consider peripheral tolerance independently from intrathymic T cell selection, a dichotomy that is challenged by observations on TE-induced tolerance. Second, they do not account for the fact that vertebrates are more readily tolerised in development than in adult life. Third, they do not explain the fact that embryonic/neonatal tolerance to foreign tissues can only be induced by HC or TE. A model of thymic selection and peripheral tolerance is developed here that resolves those problems, by assuming two classes of T cell effector functions, one being regulatory and the other aggressive. Three postulates are required: (1) both epithelial and hemopoietic cellular compartments of the thymic stroma can support both positive and negative selection of T cells, but with vastly different avidity requirements and efficiency; (2) positively selected T cells with the highest avidity that escape deletion are activated intrathymically and irreversibly committed for regulatory effector functions; (3) the functional phenotype of all other thymic emigrants is determined in the periphery upon encounter with antigen. Functional commitment in the periphery depends on the maturity stage (RTE or PMR) of the immunocompetent cell, on the nature of the antigen-presenting cells, and on the effector classes of other T lymphocytes interacting on the same presenting cell. This model explains a number of observations on experimental autoimmune disease and transplantation tolerance, and it contains several readily testable predictions.