EARLY PROGRESSION OF THYMOCYTES ALONG THE CD4/CD8 DEVELOPMENTAL PATHWAY IS REGULATED BY A SUBSET OF THYMIC EPITHELIAL-CELLS EXPRESSING TRANSFORMING GROWTH-FACTOR-BETA

Precursor cells differentiate into mature CD4(+) and CD8(+) T cells in the inductive environment of the thymus by undergoing a series of distinct developmental steps marked by expression of the coreceptor molecules CD4 and CD8. Among the earliest cells to enter the CD4/CD8 developmental pathway are CD4(-)CD8(lo) precursors cells that differentiate into CD4(+)CD8(+) thymocytes. Here we show that differentiation of precursor cells into CD4(+)CD8(+) thymocytes requires at least one cell division and that their progression through a cell cycle is specifically retarded in the thymus by interaction with thymic epithelial cells that express transforming growth factor beta (TGF-beta) proteins. We also demonstrate that TGF-beta proteins, either in solution or bound to cell membranes, can regulate cell cycle progression and differentiation of CD4(-)CD8(lo) precursor cells into CD4(+)CD8(+) thymocytes. The regulatory effect of TGF-beta is specific for CD4(-)CD8(lo) precursor cells as TGF-beta proteins do not regulate the earlier generation of CD4(-)CD8(lo) precursor cells from CD4(-)CD8(-) thymocytes. Finally, we demonstrate that TGF-beta proteins are expressed in vivo in the intact thymus on subcapsular and cortical thymic epithelium where they can contact developing CD4(-)CD8(lo) precursor cells; Thus, thymic epithelial cells expressing TGF-beta proteins can actively regulate the rate at which CD4(+)CD8(+) thymocytes are generated from CD4(-)CD8(lo) precursor cells.