Early progression of thymocytes along the CD4/CD8 developmental pathway is regulated by a subset of thymic epithelial cells expressing transforming growth factor β

Abstract

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 β (TGF- β) proteins. We also demonstrate that TGF-β 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-β is specific for CD4-CD8(lo) precursor cells as TGF-β proteins do not regulate the earlier generation of CD4-CD8(lo) precursor cells from CD4-CD8- thymocytes. Finally, we demonstrate that TGF- β 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-β proteins can actively regulate the rate at which CD4+CD8+ thymocytes are generated from CD4-CD8(lo) precursor cells.