PROTECTION FROM ANTI-TCR CD3-INDUCED APOPTOSIS IN IMMATURE THYMOCYTESBY A SIGNAL THROUGH THYMIC SHARED ANTIGEN-1/STEM CELL ANTIGEN-2/

During T cell development in the thymus, the expression of thymic shar ed antigen-1 (TSA-1)/ stem cell antigen-2 (Sca-2), a glycosylphosphati dylinositol (GPI)-anchored differentiation antigen, is developmentally regulated. The expression level of TSA-1 is the highest in most immat ure CD4(-) CD8(-) thymocytes, high in CD4(+)CD8(+) thymocytes, but bar ely detectable in mature CD4(+)CD8(-) or CD4(-)CD8(+) thymocytes and p eripheral T cells. We have previously shown that surface TSA-1 express ion in peripheral T cells is induced upon activation and that anti-TSA -1 mAb inhibits the T cell receptor (TCR) signaling pathway in activat ed T cells. In the present study, we have analyzed a role of TSA-1 in thymic selection events, especially in TCR-mediated apoptosis. In in v itro experiments, anti-TSA-1 blocked anti-CD3-induced cell death of T cell hybridomas. When anti-TSA-1 was injected into newborn mice in viv o together with anti-CD3 epsilon or anti-TCR-beta, TCR/CD3-mediated ap optosis of thymocytes was almost completely blocked. The blockade of a poptosis was defined by the inhibition of first, the decrease in total number of thymocytes; second, the decrease in percentages of CD4(+) C D8(+) thymocytes; and third, the induction of DNA fragmentation. Howev er, anti-TSA-1 did not block either steroid- or radiation-induced apop tosis, indicating that a signal via TSA-1 does not inhibit a common pa thway of thymocyte apoptosis. Since TCR-mediated apoptosis is pivotal in thymic ontogeny, these results suggest that TSA-1/Sca-2 is an impor tant cell surface molecule regulating the fate of a developing T cell.