Intrathymic Presentation of Circulating Non - Mhc Antigens

The generation of the T cell repertoire, the site and mechanism of T cell subset bifurcation, and the selective constraints exerted on the developing repertoire to ensure self-tolerance are still poorly understood. The assignment of these events to either the pre-, intra-, or postthymic stages of T cell maturation has been aided by the recent development of mAb to the antigen-specific T cell receptor(s) (1), and the cloning of genes encoding this receptor(s) (2). The available data strongly suggest that the differentiation events mentioned above take place during intrathymic T cell differentiation. T cell receptor gene rearrangement and subsequent T cell receptor surface expression seem to occur early during thymic differentiation. It is likely that ~50% of cortical thymocytes already express the receptor heterodimer and the T3 complex on the cell surface (3, 4). Given the low frequency of T cell precursors among cortical thymocytes and the low exit rate of thymocytes (5-8), T cell receptor expression is obviously a necessary but not a sufficient criterion for positive T cell selection. Since early migrants display a T cell repertoire similar to that of peripheral T cells (9), the development of the T cell repertoire can now be more precisely placed between the intrathymic stage where T cells first express their recognition molecules, and their exit. Assuming the initial generation of a random T cell repertoire, it follows that important selection processes must operate intrathymically on the developing T cell population. Thymocyte-stromal cell interactions are thought to be, at least in part, involved in these differentiation and selection events (10, 11). Three different types of such intercellular interactions have been recently characterized in more detail (12, 13), namely associations between thymocytes and (a) cortical epithelial cells (thymic nurse cells, TNC), 1 (b) cortical macrophages, and (c) medullary dendritic cells (DC); the in vitro isolates of the latter two interactions are referred to as thymocyte rosettes, T-ROS. Evidence has been obtained that T cells specifically and nonrandomly associate with these distinct stromal cells in vivo, and that TNC and T-ROS represent the correlate