Mireille Dardenne

Characterization of the Extracellular Matrix—Containing Giant Perivascular Spaces in the NOD Mouse Thymus

It is well established that the NOD mouse develops T-cell-dependent autoimmune type I diabetes that is abolished by neonatal Tx and enhanced by Tx at weaning. In a previous study, we demonstrated that the NOD thymus displays various abnormalities in the microenvironmental compartment, including abnormal distribution of epithelial cell subsets, precocious decline in thymic hormone production and formation of giant PVS. These latter structures present an internal ECM-containing network filled with T-cells and to a lesser extent B-cells. Herein we have investigated further the giant PVS and particularly the origin of the T-cells that colonize these structures. The thymic origin of intra-PVS T-cells was ascertained by distinct protocols. First, sublethal X-ray irradiation or HC treatment leading to cortical thymocyte depletion showed that intra-PVS lymphocytes were resistant, similar to medullary thymocytes. Second, adoptive transfer experiments that used newborn or adult irradiated Thy-1 congenic recipients demonstrated that intra-PVS accumulation of T-cells did not result from the reentry of peripheral mature T-cells into the thymus. Third, kinetic studies that used BrdUrd pulse chase revealed that labeled intra-PVS cells appear late, simultaneously with medullary thymocytes, and remain only transiently within the PVS. Thus, the kinetics of T-cell reconstitution of PVS was compatible with the progressive differentiation of T-cell precursors originating from the thymic cortex. In this respect, thegiant PVS of the NOD mouse thymus may represent a useful model to study the relationships between trafficking thymocytes and ECM proteins.

Zinc and Thymulin

Thymulin is a thymic hormone produced by thymic epithelial cells (TEC) known to induce intra- and extra thymic T cell differentiation. It is a nonapeptide whose biological activity and antigenicity depend upon the presence of zinc, which also induces conformational changes in the molecule as demonstrated by RMN studies. The presence of zinc and metallothionein have been demonstrated with TEC which produce the peptide, suggesting that the molecule is secreted in its active zinc-containing form.

Thymulin: biochemistry, biology and therapeutical applications

Thymulin is a pharmacologically active metallononapeptide inducing the differentiation of T cells and enhancing several functions of the various T cell subsets in normal or partially thymus-deficient recipients. Its effect on suppressor T cells is, so far, the most remarkable and should be the first to find useful clinical applications. The peptide is a natural hormone, available in synthetic form. It is not toxic and one may foresee its clinical use as one of the major immunoregulatory agents in the near future.

Recent Data on the Structure, Localization and Function of the Serum Thymic Factor (Thymulin)

The serum thymic factor (FTS) or thymulin is a thymic hormone which has been characterized by its capacity to induce T cell markers on bone marrow cells.1 It is a nonapeptide whose amino acid sequence has been determined.2 We have recently demonstrated the existence of two forms of FTS: the first one without zinc and biologically inactive, and another which binds zinc and is biologically active, for which we recently proposed the name of thymulin.3 Practically thymulin or FTS-Zn represents the natural zinc-coupled peptide; the use of “FTS” is reserved for the synthetic material not coupled to the metal.