BB Enhanced CD 4 T Cell Responsiveness in

had enhanced cell division compared with wild-type cells and displayed augmented clonal expansion during the primary response. This was not due to a developmental defect as 4-1BB-deficient CD4 cells could respond normally to Ag in vitro. These results demonstrate that the absence of 4-1BB can make CD4 T cells hyperresponsive to protein Ag in vivo, suggesting a new unappre-ciated negative regulatory role of 4-1BB when expressed on a T cell. T cells need costimulation for activation, proliferation, and survival, which prevents the induction of tolerance and induces T cell immunity (1). Costimulatory molecules can be divided into two main groups: the Ig superfamily and the TNFR superfamily (2, 3). The 4-1BB (CD137), a member of the TNFR superfamily, was originally found on activated T cells, but has since been identified on other immune cells, including NK cells, monocytes, neutrophils, and dendritic cells (DC) 3 (4 –9). The 4-1BB ligand (4-1BBL) is largely expressed on APCs, such as B cells, macrophages, and DC (8, 10). The interaction of 4-1BB with 4-1BBL was proposed to preferentially costimulate CD8 T cells (11), but a number of studies have demonstrated that it also might play a role in CD4 T cell responses. Engaging 4-1BB on naive CD4 T cells with 4-1BBL-transfected fibroblast cells promoted proliferation and cell cycle progression and suppressed apoptosis (12). The 4-1BBL augmented primary responses of CD4 T cells in the absence of CD28 signaling, and 4-1BB agonistic Ab enhanced CD4 T cell responses in vitro and in vivo (13, 14). Moreover, 4-1BB ligation by single-chain Fv fragments of anti-4-1BB Ab on tumor cells promoted enhanced tumor rejection in a CD4 T cell-dependent manner (15). These results have therefore indicated a positive costimulatory role for 4-1BB on CD4 T cells. In contrast, it has been reported that 4-1BB ligation has either no specific role or even a negative role in regulating CD4 T cells. For example, 4-1BBL Ϫ/Ϫ mice generated normal CD4 T cell responses after lymphocytic choriomen-ingitis virus and influenza infection, although CD8 T cell responses were down-regulated in those mice (16, 17). In addition, 4-1BB agonistic Ab treatment unexpectedly led to suppressed pathogenic CD4 T cell responses in several autoimmune disease models, including experimental autoimmune encephalomyelitis, lupus, and collagen-induced arthritis (18 –21). Thus, the role of 4-1BB, especially in vivo, appears to be quite complex and may vary depending upon the inflammatory conditions. The 4-1BB Ϫ/Ϫ mice develop normally, …