Thymic T-cell tolerance of neuroendocrine functions: Physiology and pathophysiology

Intimate interactions between the two major systems of cell-to-cell communi cation, the neuroendocrine and immune systems, play a pivotal role in homeo stasis and developmental biology. During phylogeny as well as during ontoge ny, the molecular foundations of the neuroendocrine system emerge before th e generation of diversity within the system of immune defenses. Before reac ting against non-self infectious agents, the immune system has to be educat ed in order to tolerate the host molecular structure (self). The induction of self-tolerance is a multistep process that begins in the thymus during f etal ontogeny (central tolerance) and also involves anergizing mechanisms o utside the thymus (peripheral tolerance). The thymus is the primary lymphoi d organ implicated in the development of competent and self-tolerant T-cell s. During ontogeny, T-cell progenitors originating from hemopoietic tissues (yolk sac, fetal liver, then bone marrow) enter the thymus and undergo a p rogram of proliferation, T-cell receptor (TCR) gene rearrangement, maturati on and selection. Intrathymic T-cell maturation proceeds through discrete s tages that can be traced by analysis of their cluster differentiation (CD) surface antigens. It is well established that close interactions between th ymocytes (pre-T-cells) and the thymic cellular environment are crucial both for T-cell development and for induction of central self-tolerance. Partic ular interest has focused on the ability of thymic stromal cells to synthes ize polypeptides belonging to various neuroendocrine families. The thymic r epertoire of neuroendocrine-related precursors recapitulates at the molecul ar level the dual role of the thymus in T-cell negative and positive select ion. Thymic precursors not only constitute a source of growth factors for c ryptocrine signaling between thymic stromal cells and pre-T-cells, but are also processed in a way that leads to the presentation of self-antigens by (or in association with) thymic major histocompatibility complex (MHC) prot eins. Thymic neuroendocrine self-antigens usually correspond to peptide seq uences highly conserved during the evolution of their corresponding family. The thymic presentation of some neuroendocrine self-antigens does not seem to be restricted by MHC alleles. Through the presentation of neuroendocrin e self-antigens by thymic MHC proteins, the T-cell system might be educated to tolerate main hormone families. More and more recent experiments suppor t the concept that a defect in thymic tolerogenic function is implicated as an important factor in the pathophysiology of autoimmunity.