Brief Definitive Report Protection from Anti-TCR/CD3-induced Apoptosis in Immature Thymocytes by a Signal through Thymic Shared Antigen-I/Stem Cell Antigen-2 By

During T cell development in the thymus, the expression ofthymic shared antigen-1 (TSA-1)/ stem cell antigen-2 (Sca-2), a glycosylphosphatidylinositol (GPI)-anchored differentiation antigen, is developmentally regulated. The expression level of TSA-1 is the highest in most immature CD4CD8thymocytes, high in CD4 + CD8 + thymocytes, but barely detectable in mature CD4+CD8 or CD4CD8 + thymocytes and peripheral T cells. We have previously shown that surface TSA-1 expression in peripheral T cells is induced upon activation and that anti-TSA-1 mAb inhibits the T cell receptor (TCR) signaling pathway in activated T cells. In the present study, we have analyzed a role of TSA-1 in thymic selection events, especially in TCP,-mediated apoptosis. In in vitro experiments, anti-TSA-1 blocked anti-CD3-induced cell death o f T cell hybridomas. When anti-TSA-1 was injected into newborn mice in vivo together with anti-CD3e or anti-TCR-[3, TCR/CD3-media ted apoptosis of thymocytes was almost completely blocked. The blockade of apoptosis was defined by the inhibition of, first, the decrease in total number of thymocytes; second, the decrease in percentages of CD4 + CD8 § thymocytes; and third, the induction of DNA fragmentation. However, anti-TSA-1 did not block either steroidor radiation-induced apoptosis, indicating that a signal via TSA-1 does not inhibit a common pathway of thymocyte apoptosis. Since TCR-mediated apoptosis is pivotal in thymic ontogeny, these results suggest that TSA-1/Sca-2 is an important cell surface molecule regulating the fate of a developing T cell.