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The dual physiological role of the thymus in T cell positive and negative selection appears prominent in the establishment of appropriate host immune defenses. However, the cellular and molecular mechanisms underlying those thymic functions begin only to be understood. On the basis of our previous investigations about the thymic expression of different neuroendocrine-related signals, we have advanced a model which transposes at the peptide level the intervention of this primary lymphoid organ in both T cell positive and negative selective processes. There is now ample evidence that the thymic subcapsular and medullary epithelium is the site for synthesis of neurohypophysial (NHP)-related peptides (reviewed in Geenen et al., 1992a). We have also demonstrated that the epithelial component of thymic "nurse" cells (TNC) synthesizes NHP-related peptides and expresses a neuroendocrine-like phenotype (Geenen et al., 1988a). This observation was a remarkable example of the intimate neuroendocrine-immune interactions that take place during T cell ontogeny. Further immunocytochemical analyses have confirmed that one dominant NHP-related epitope belongs to the oxytocin (OT) lineage of the NHP peptide superfamily (Robert et al., 1991, 1992). The intrathymic coexpression of this OT-like epitope with a neurophysin protein domain is a strong argument for a local synthetic process similar to the hypothalamo-NHP one. However, the absence of ir-OT in secretory granules of thymic epithelial cells (TEC), as well as of NHP-related peptides in the supernatant of TEC cultures questioned the application to the thymus of the classical neurosecretory model established for hypothalamic magnocellular neurons (Scharrer & Scharrer, 1944).(ABSTRACT TRUNCATED AT 250 WORDS)