Thymus-dependent T cell tolerance of neuroendocrine functions: principles, reflections, and implications for tolerogenic/negative self-vaccination.

Under the evolutionary pressure exerted by the emergence of adaptive immunity and its inherent risk of horror autotoxicus, the thymus appeared some 500 million years ago as a novel lymphoid structure able to prevent autoimmunity and to orchestrate self-tolerance as a cornerstone in the physiology of the immune system. Also, the thymus plays a prominent role in T cell education to neuroendocrine principles. Some self-antigens (oxytocin, neurotensin, insulin-like growth factor 2 [IGF-2]) have been selected to be predominantly expressed in thymic epithelium and to be presented to thymus T cells for educating them to tolerate other antigens related to them. In the insulin family, IGF2 is dominantly transcribed in cortical (c) and medullary (m) thymic epithelial cells (TECs), whereas the insulin gene (INS) is expressed at low level by only a few subsets of mTECs. Intrathymic transcription of both IGF2 and INS is under the control of the autoimmune regulator (Aire) gene. The highest concentrations of IGF-2 in the thymus explain why this peptide is much more tolerated than insulin, and why tolerance to IGF-2 is so difficult to break by active immunization. The high level of tolerance to IGF-2 is correlated to the development of a tolerogenic/regulatory profile when the sequence B11-25 of IGF-2 (homologous to the autoantigen insulin B9-23) is presented to DQ8+ type 1 diabetic patients. Since subcutaneous and oral insulin does not exert any tolerogenic properties, IGF-2 and other thymus self-antigens related to type 1 diabetes (T1D) should be preferred to insulin for the design of novel specific antigen-based preventive approaches against T1D.