Presentation of neuroendocrine self in the thymus: a necessity for integrated evolution of the immune and neuroendocrine systems

During evolution, from ancestor thymoids scattered in gill baskets of the lamprey, the first unique thymus appeared in jawed cartilaginous fishes around 450-500 millions years ago, concomitantly or shortly after the emergence of recombinase-dependent adaptive immunity. The major biological function of the thymus is to generate a diverse repertoire of T cell receptors that are self tolerant. The thymus achieves this role by using two complementary and intimately associated mechanisms: apoptotic deletion of T cell clones bearing a TCR with high affinity for self-antigens presented by MHC proteins on thymic epithelial cells (TECs) and dendritic cells (DCs); and generation of self-antigen-specific natural regulatory T (nT(reg)) cells. Moreover, the escape from thymic central self-tolerance plays a primary role in the development of autoimmune diseases that are a significant burden for the quality of life and health-care cost. Our new knowledge in thymus physiology and physiopathology is currently translated into innovative therapeutic strategies against these devastating chronic diseases.