A Model for Developmentally Acquired Thymus‐Dependent Tolerance to Central and Peripheral Antigens

Abstract

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.

Repertoire Requirements of CD4+ T Cells That Prevent Spontaneous Autoimmune Encephalomyelitis

“…These discrepancies indicate that CD4 ϩ regulatory T cells are heterogeneous, and different experimental systems reveal the predominant effect of regulatory T cells displaying different properties. In spontaneous EAE, our data supports a model in which regulatory T cells display regulatory properties upon leaving the thymus, as has been previously proposed for transplantation tolerance models (52).…”

Regulatory CD4 T Cells Control the Size of the Peripheral Activated/Memory CD4 T Cell Compartment

“…Several studies using different experimental systems have shown that CD4 ϩ CD8 Ϫ thymocytes can also exert regulatory function (33-37). The intrathymic generation of regulatory T cells (37) supports the idea that these cells are self-reactive (38).…”

Neuroprotective autoimmunity: Naturally occurring CD4 + CD25 + regulatory T cells suppress the ability to withstand injury to the central nervous system

“…As a corollary, postinjury neuronal survival was improved after the rats were immunized as adults with myelin proteins emulsified in adjuvant or after depletion of regulatory (suppressor) CD4 ϩ CD25 ϩ T cells. Naturally occurring regulatory T cells [apparently the cells that in early studies were identified as thymus-induced suppressor CD4 T cells (17)(18)(19)] may be viewed as safeguards against autoimmune disease. At the same time, as suggested by findings during the past few years (3,5,7) and as shown in the present work, autoimmune T cells are required as safeguards of CNS maintenance in the day-to-day need to cope with stressful conditions.…”