DEFECTIVE DEVELOPMENT OF THYMOCYTES OVEREXPRESSING THE COSTIMULATORY MOLECULE, HEAT-STABLE ANTIGEN

Heat-stable antigen (HSA) is a small, glycosyl phosphatidylinositol-an chored protein that can act as a costimulatory molecule for antigen-de pendent activation of helper T cells. In addition to being expressed o n antigen-presenting B cells, HSA is also expressed during the initial stages of T cell development in the thymus. HSA levels are very high on immature CD4(-), CD8(-) double negative thymocytes, but are reduced on CD4(+), CD8(+) double positive cells undergoing selection in the t hymus, and are entirely eliminated when these cells differentiate into immunologically competent CD4(+) or CD8(+) single positive T cells. T o examine the potential. roles of this molecule in T cell development and selection, we generated transgenic mice in which HSA was highly ex pressed on all classes of thymocytes. The consequence of deregulated H SA expression was a pronounced reduction in the numbers of double posi tive and single positive thymocytes, whereas the numbers of their doub le negative precursors were largely unaffected. These results demonstr ate that downregulation of HSA expression at the double positive stage is a critical event in thymocyte development. The depletion of thymoc ytes resulting from HSA overexpression begins at the same time as the onset of negative selection, suggesting that HSA may provide signals t hat contribute to determining the efficiency of this process.