Abdellah Benhida

The Recognition of Hypothalamo-Neurohypophysial Functions by Developing T Cells

Neuropeptide signals and specific neuropeptide receptors have been described in the thymus supporting the concept of a close dialogue between the neuroendocrine and the immune systems at the level of early T-cell differentiation. In this paper, we review recent data about neurohypophysial (NHP)-related peptides detected in the thymus from different species. We suggest that we are dealing in fact with other member(s) of the NHP hormone family, which seems to exert its activity locally through a novel model of cell-to-cell signaling, that of cryptocrine communication. This model involves exchange of signals between thymic epithelial cells and developing thymocytes. The NHP-related peptides have been shown to trigger thymocyte proliferation and could induce immune tolerance of this highly conserved neuroendocrine family.

Developmental and evolutionary aspects of thymic T-cell education to neuroendocrine self

Thymic epithelial cells, including nurse cells (TECs/TNCs), from various species synthesize neuroendocrine-related precursors belonging to neurohypophysial, tachykinin and insulin hormone families. The thymic repertoire of neuroendocrine-related polypeptides illustrates at the molecular level the paradoxical role of the thymus in both T cell positive and negative selection. On the one hand, these precursors are a source of signals which interact with neuroendocrine-type receptors expressed by target pre-T cells according to the cryptocrine type of cell-to-cell signaling. On the other hand, the same precursors constitute a source of self-antigens which are presented to pre-T cells by the thymic major histocompatibility complex system. Basically, the model of thymic T cell education to neuroendocrine self was established by the identification in TECs/TNCs of immunoreactive (ir) oxytocin as the self-antigen of the neurohypophysial family. Nevertheless, through the expression in TECs/TNCs of ir-neurokinin A and ir-insulin-like growth factor-II, the model also applies to the tachykinin and insulin hormone families.

Thymic neuroendocrine self peptides and T cell selection.

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 families1,2,3,4,5. 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.