Various costimulatory molecules modulate T cell function during immune responses. We and others have proposed that 4-1BB and its ligand are an essential part of any T cell response. However, an understanding of the precise mode of action of 4-1BB is lacking. Furthermore, at what stage(s) during a T cell response 4-1BB is utilized and how its engagement modulates clonal expansion, effector cell development, or memory cell development is not known. The projects proposed here will help define the functioning of 4-1BB in CD8+ T cell responses. Initially, factors regulating the expression of 4-1BB and its ligand will be clearly defined. Then, the fine function of 4-1BB in a CD8+ T cell response to antigen and costimulatory ligand will be uncovered using 4-1BBL transfected APCs and the 4-1BB:Fc blocking agent. Discrepancies in the literature as to which subset (CD4+ or CD8+) preferentially utilize 4-1BB will be clarified by antibody-mitogen activation studies. Lastly, the functioning of 4-1BB in intact organisms will be addressed through several in vivo studies. Recent findings implicate 4-1BB as playing an immunoregulatory role in several immune responses, including anti-tumor immunity. 4- 1BB most likely has a strong immunoregulatory role in vivo, and therefore, a more complete understanding of its functioning will have implications for the treatment of cancer, transplantation rejection, and autoimmunity, as well as the development of vaccines.
