There are several well-characterized T cell costimulatory signals, none of which has been studied more than CD28. CD28 ligation in conjunction with TCR signaling induces potent T cell activation as manifested by the secretion of IL-2 and robust proliferation. Our studies of 4-1 BB, another potent T cell costimulatory molecule, have shown several interesting parallels, but also profound differences. Ligation of 4-1BB on activated T cells induces similar functions, such as heightened cytokine secretion and proliferation. In contrast, however, 4-1BB is not expressed on resting cells. Perhaps the most dramatic difference, however, is in our in vivo models, where we have demonstrated that 4-1BB costimulation, but not CD28 costimulation, induces CD8 T cell long-term survival. The mechanics of how survival develops is unknown, but is a major focus of this proposal. For example, do T cells divide throughout the activation-induced cell death phase and accumulate in massive numbers such that many of them avoid death by dilution, or are they inherently resistant to death stimuli because of 4-1BB stimulation? This issue is addressed, as is the question of what is the underlying mechanism of survival. We will examine which cell populations """"""""help"""""""" the 4-1BB stimulated T cells survive and uncover the requirements for survival after Ag stimulation and costimulation. As an initial clue it is clear that adjuvants and adjuvant-inducing cytokines synergize with 4-1BB stimulation to induce high levels of long term T cell survival. Importantly, preliminary data show that many of the surviving cells possess a memory phenotype. Experiments are designed to determine which cytokines are key and how the cytokines function. Perhaps what is most striking is that the 4-1BB-rescued CD8 T cells behave as inhibitory cells rather than typical memory cells which have been costimulated by prototypical costimulatory molecules. It is shown that the rescued cells possess the ability to block CD4 T cell proliferation and IL-2 production. These results are addressed in great detail and ultimately will lend credence to the interesting notion that not all costimulatory signals function in congruence. ? ?
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