The Thymic Repertoire of Neuroendocrine-Related Self Antigens: Biological Role in T-Cell Selection and Pharmacological Implications

Abstract

Thymic epithelium, including nurse cells (TEC/TNC), as well as other thymic stromal cells (macrophages and dentritic cells), express a repertoire of polypeptide belonging to various neuroendocrine protein families (such as the neurophypophysial, tachykinin, neurotensin and insulin families). A hierarchy of dominance exists in the organization of the thymic repertoire of neuroendocrine precursors. Oxytocin (OT) is more expressed in the TEC/TNC than vasopressin (VP); insulin-like growth factor 2 (IGF-2) thymic expression predominates over IGF-1, and much more over (pro)insulin. Thus, OT was proposed to be the self antigen of the neurohypophysial family, and IGF-2 the self antigen precursor of the insulin family. The dual role of the thymus in T-cell life and death is recapitulated at the level of the thymic neuroendocrine protein repertoire. Indeed, thymic polypeptides behave as accessory signals involved in T-cell development and positive selection according to the cryptocrine model of signaling. Moreover, thymic neuroendocrine polypeptides are the source of self antigens presented by thymic MHC molecules to developing pre-T cells. This presentation might induce the negative selection of T cells bearing a randomly rearranged antigen receptor (TCR) oriented against neuroendocrine families. Using an animal model of autoimmune type 1 diabetes (BB rat), we have shown a defect in intrathymic expression of the self antigen of the insulin family (IGF-2) and in IGF-2-mediated T-cell education to recognize and tolerate the insulin family. Altogether these studies have enlighted the crucial role played by the thymus in the induction of the central self tolerance of neuroendocrine families. The tolerogenic properties of thymic self peptides could be used in a novel type of vaccination for the prevention of autoimmune diseases.

Oxytocin in cardiac ontogeny

“…In contrast to its action on tumoral cells, a mitogenic action of OT by phosphorylation and activation of mitogen-activated protein kinase has been described in myometrium (31). OT stimulates the proliferation of thymocytes (32,33), the prostate epithelium (34), and trophoblasts (35). OT has also been reported to enhance myoepithelial cell differentiation and proliferation in the mouse mammary gland (36).…”

Transplantation Tolerance and Autoimmunity After Xenogeneic Thymus Transplantation

“…For insulin, there is evidence for expression at the protein level (57)(58)(59). Thus, thymus epithelium is now generally believed to be very important for the induction of tissue-specific tolerance (60 -67).…”

Quantification of T cell receptor rearrangement excision circles to estimate thymic function: an important new tool for endocrine-immune physiology

“…The integration of the thymus in endocrine physiology did not completely vanish, however, and the primary lymphoid organ is crucially located at the crossroad between the major systems of cell-to-cell communication, the neuroendocrine and immune systems. Through transcription of neuroendocrine genes in the thymus stromal network and expression of cognate receptors by immature T cells, the neuroendocrine system regulates early T cell differentiation (reviewed in Geenen et al 1999Geenen et al , 2003. Glucocorticoids also are synthesised in thymic epithelium and are able to impact on thymocyte development (reviewed in Ashwell et al 2000).…”