4‐1BB‐dependent inhibition of immunosuppression by activated CD4+CD25+ T cells

4‐1BB (CD137) is a costimulatory molecule involved in the activation and survival of CD4, CD8, and natural killer cells. Although a great deal has been learned as to how 4‐1BB‐mediated signaling governs the immunity of conventional T cells, the functional role of 4‐1BB in the context of CD4+CD25+ regulatory T cell (Tr) activation is largely unknown. Using 4‐1BB‐intact and ‐deficient mice, we investigated the effect of the 4‐1BB/4‐1BB ligand pathway on the suppressive function of Tr cells. Our data indicate that although 4‐1BB is expressed on Tr cells, its contribution to their proliferation is minimal. We also showed that signaling through the 4‐1BB receptor inhibited the suppressive function of Tr cells in vitro and in vivo. It is interesting that anti‐4‐1BB‐mediated but not anti‐GITR‐directed inhibition was more potent when Tr cells were preactivated. Collectively, these data indicate that 4‐1BB signaling is critical in Tr cell immunity.