Co-stimulation of antigen-specific CD4 T cells by 4-1BB ligand

4-1BB is a member of the TNF receptor family predominantly expressed on act ivated T cells, and binds an inducible ligand found on B cells, macrophages and dendritic cells. Whereas ligation of 4-1BB has been shown to enhance r esponse of purified CD8 T cells to mitogens, and to augment NK activity and generation of cytotoxic T lymphocytes in vivo, there are little direct dat a on 4-1BB action during CD4 responses. Using pigeon cytochrome c-presentin g fibroblast antigen-presenting cells transfected with 4-1BB ligand (4-1BBL ), we show that engaging 4-1BB on naive CD4 cells promotes proliferation, c ell cycle progression and IL-2 secretion, and suppresses cell death, all to a similar extent as B7-1 engagement of CD28. In addition, 4-1BBL synergize s with B7 and ICAM to enhance naive CD4 proliferation when antigen is limit ing. 4-1BBL alone, and to a greater extent with 87, also augmented IL-2 sec retion resting antigen-experienced CD4 cells, as typified by T helper clone s, whereas short-term effector cells showed similar levels of proliferation and cytokine secretion regardless of whether 4-1BB was engaged. A major ro le in augmenting lFN-gamma, IL-4 or IL-5 was not demonstrated. Blocking stu dies with activated B cells presenting antigen showed that 4-1BB participat es in promoting IL-2 production by resting CD4 cells, confirming that 4-1BB L can play a role in antigen-specific CD4 T cell responses.