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 l~ 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 fl (TGF-fl) proteins. We also demonstrate that TGF-fl proteins, either in solution or bound to cell membranes, can regulate cell cycle progression and differentiation of CD4-CD81~ precursor cells into CD4+CD8 + thymocytes. The regulatory effect of TGF-B is specific for CD4-CD8 l~ precursor cells as TGF-fl proteins do not regulate the earlier generation of CD4-CD81~ precursor cells from CD4-CD8thymocytes. Finally, we demonstrate that TGF-fl proteins are expressed in vivo in the intact thymus on subcapsular and cortical thymic epithelium where they can contact developing CD4-CD81~ precursor cells. Thus, thymic epithelial cells expressing TGF-~ proteins can actively regulate the rate at which CD4 + CD8 § thymocytes are generated from CD4-CD8 l~ precursor cells.

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