RESCUE OF THYMOCYTES FROM GLUCOCORTICOID-INDUCED CELL-DEATH MEDIATED BY CD28 CTLA-4 COSTIMULATORY INTERACTIONS WITH B7-1/B7-2/

During the differentiation of thymocytes to mature T cells the process es of positive and negative selection result in signals that either pr otect thymocytes from cell death, or delete, through apoptosis, thymoc ytes with self-reactive T cell receptors (TCR). Glucocorticoids have b een shown to induce thymocyte apoptosis and are produced within the th ymic microenvironment. Furthermore, steroid-induced apoptosis of thymo cytes has been suggested as a potential mechanism for removal of nonse lected thymocytes. In this report, we demonstrate that thymocytes can be rescued from glucocorticoid-induced apoptosis by incubation with ce lls that express high levels of B7-1 or B7-2. In addition, the ability to be rescued by B7-1 and/or B7-2 can precede expression of the TCR. We demonstrate that CD3(+)-depleted or CD3(+)/TCR-beta(+)-doubly deple ted thymocytes can be rescued from glucocorticoid-induced apoptosis th rough the interaction of CD28 or CTLA-4 on thymocytes with cells beari ng high levels of B7-1 or B7-2. Furthermore, these transfected cells a re major histocompatibility complex (MHC) class II negative and, while they may express MHC class I, there is no preferential rescue of CD8( +) thymocytes in the presence of glucocorticoids. Together, these data suggest that the rescue of thymocytes from glucocorticoids can be ind ependent of the TCR. We also demonstrate that, in addition to CD28, CT LA-4 is expressed on thymocytes, suggesting that rescue from glucocort icoid-induced cell death can be mediated by both CD28 and CTLA-4. A CT LA-4Ig fusion protein which binds to both B7-1 and B7-2 was shown to c ompletely block the rescue of thymocytes from glucocorticoid-induced c ell death. Therefore, we conclude that interactions between B7-1/B7-2 and CD28/CTLA-4 are sufficient and necessary for rescue of thymocytes from glucocorticoid-induced cell death.