Maturation versus death of developing double-positive thymocytes reflects competing effects on Bcl-2 expression and can be regulated by the intensityof CD28 costimulation

Immature double-positive (DP) thymocytes mature into CD4(+)CD8(-) cells in response to coengagement of TCR with any of a variety of cell surface "coin ducer" receptors, including CD2, In contrast, DP thymocytes are signaled to undergo apoptosis by coengagement of TCR with CD28 costimulatory receptors , but the molecular basis for DP thymocyte apoptosis by TCR plus CD28 coeng agement is not known. In the present study, we report that TCR plus CD28 co engagement does not invariably induce DP thymocyte apoptosis but, depending on the intensity of CD28 costimulation, can induce DP thymocyte maturation . We demonstrate that distinct but interacting signal transduction pathways mediate DP thymocyte maturation signals and DP thymocyte apoptotic signals . Specifically, DP maturation signals are transduced by the extracellular s ignal-related kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and up-regulate expression of the antiapoptotic protein Bcl-2. In contrast, the apoptotic response stimulated by CD28 costimulatory signals is mediate d by ERK/MAPK-independent pathways, Importantly, when TCR-activated thymocy tes are simultaneously coengaged by both CD28 and CD2 receptors, CD28 signa ls can inhibit ERK/MAPK-dependent Bcl-2 protein up-regulation, Thus, there is cross-talk between the signal transduction pathways that transduce apopt otis and maturation responses, enabling CD28-initiated signal transduction pathways to both stimulate DP thymocyte apoptosis and also negatively regul ate maturation responses initiated by TCR plus CD2 coengagement.