NEGATIVE SELECTION OF CD4(-CELL RECEPTOR-INDUCED APOPTOSIS REQUIRES ACOSTIMULATORY SIGNAL THAT CAN BE PROVIDED BY CD28()CD8(+) THYMOCYTES BY T)

CD4(+)CD8(+) thymocytes expressing self-reactive T cell antigen recept ors (TCR) are deleted in the thymus as a consequence of TCR/self-antig en/major histocompatibility complex interactions. However, the signals that are necessary to initiate clonal deletion have not yet been clar ified. Here we demonstrate that TCR engagement does not efficiently in duce apoptosis of CD4(+)CD8(+) thymocytes, although it generates signa ls that increase expression of CD5, a thymocyte differentiation marker . In fact, TCR signals fail to induce thymocyte apoptosis even when au gmented by simultaneous engagement with CD4 or lymphocyte function 1-a ssociated molecules. In marked contrast, signals generated by engageme nt of both TCR and the costimulatory molecule CD28 potently induce apo ptosis of CD4(+)CD8(+) thymocytes. Thus, the present results define a requirement for both TCR and costimulatory signals for thymocyte apopt osis and identify CD28 as one molecule that is capable of providing th e necessary costimulus. These results provide a molecular basis for di fferences among cell types in their ability to mediate negative select ion of developing thymocytes.