Thymic Neuroendocrine Self Peptides and t Cell Selection

Abstract

Our previous studies have shown that the thymic epithelial cells (TEC) of different animal species were the site for synthesis of polypeptide precursors belonging to the neurohypophysial (NHP), tachykinin (TK), and insulin neuroendocrine families^1,2,3,4,5. However, at least in basal conditions, cultured human TEC do not secrete NHP-related peptides, neurokinin A (NKA) nor insulin-like growth factor 2 (IGF2); the existence of a classical secretory pathway in the thymic epithelium may thus be questioned. We also failed to detect immunoreactive (ir) thymic NHP-related peptides in classical secretory granules and a very elegant recent study has demonstrated that ir oxytocin (OT), the dominant thymic NHP-related peptide, was located diffusely in the cytosol and in clear vacuoles of murine TEC⁶. The term cryptocrine has been introduced in the word-list of Endocrinology to describe this particular type of cell-to-cell signaling in specialized microenvironments constituted by large “nursing” epithelial cells (like TEC/TNC in the thymus, or Sertoli cells in the testis) enclosing cell populations that migrate and differentiate at their very close contact (respectively, T cells and spermatids)⁷. In the general evolution of cell-to-cell communication, the cryptocrine type of signaling is located at a rather primitive step, between intercellular adhesion and paracrine exchanges of soluble signals. Moreover, in the thymus, the cryptocrine stage is closely associated with the presentation of the self molecular structure to the developing T cell system. Therefore, the thymus appears as one crucial meeting point for the two major systems of intercellular communication: therein, the endocrine system may influence the early steps of the immune response, whereas the immune system is educated in self neuroendocrine principles⁸. We would like to present here our experimental arguments that permit to transpose at the level of the thymic repertoire of neuroendocrine-related peptides the dual physiological role of this primary lymphoid organ in T cell positive and negative selection.