Analysis of expression and function of the costimulatory molecule 4-1BB inalloimmune response

Background. 4-1BB (CD137) is a T cell costimulatory molecule that promotes T cell activation. In this study, we investigated the role of 4-1BB costimu lation in allogeneic T cell responses. Methods. Vascularized heart transplantation, allogeneic mixed leukocyte rea ction (MLR), and graft versus host disease models were used to examine 4-1B B and 4-1BBL expression. In addition, agonistic anti-4-1BB antibodies were used in MLR to functionally analyze T cell responses. Results. Using a heart transplant model, we found that 4-1BB and 4-1BBL tra nscripts were both expressed in rejecting cardiac grafts. In the allogeneic MLR, 4-1BB was expressed on both activated CD4 and CD8 T cells and 4-1BB w as expressed on T cells after multiple cell divisions in vivo. Functionally , 4-1BB was a potent stimulator of proliferation, cytokine secretion, and C D25 expression by CD8 T cells, but 4-1BB signals had a weak effect on the p roliferation of CD4 T cells. Because 4-1BB promoted the secretion of IL-2 a nd the expression of CD25 on CDS T cells, we investigated whether IL-2 was the only factor whereby 4-1BB signals induced CD8 T cell proliferation. Alt hough IL-2 was required for optimal CD8 T cell proliferation, 4-1BB also co stimulated CD8 T cell proliferation independently of IL-2. Conclusions. This study demonstrates that 4-1BB is expressed on activated, maximally divided T cells and shows that 4-1BB promotes CD8 T cell prolifer ation by enhancing signals through the IL-2 receptor and by other mechanism s independent of the IL-2 pathway.