Understanding the mechanism of 4-1BB costimulation

University Of Connecticut Sch Of Med/Dnt, Farmington CT

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Abstract

DESCRIPTION (provided by investigator): It is well documented that two signals, one through the T cell receptor and a second from a costimulatory molecule, are more efficient at stimulating T cells then one signal alone. 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 lL-2 and robust proliferative response. Our studies of 4-1 BB another potent T cell costimulatory molecule, have shown several interesting parallels, but also profound differences. Ligation of 4-1 BB on activated T cells induces similar functions such as heightened cytokine secretion and proliferation. In contrast, however, 4-1 BB is not expressed on resting cells. Perhaps the most dramatic difference in our in vivo models is that unlike CD28 ligation, 4-1 BB stimulation 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 4-1 BB 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 4-1 BB stimulation to induce huge levels of long term T cell survival. Experiments are designed to determine which cytokines are key and how the cytokines function. Perhaps what is most striking is that the 4-1 BB-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 lL-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.