The tumour necrosis factor (TNF) receptor family member 4-1BB, and its TNF family ligand, 4-1BBL, have been thoroughly investigated as potent modulators of the CD8 T cell response. During a viral infection, 4-1BBL on APC, binding to 4-1BB on activated T cells mediates survival signaling in activated and memory CD8 T cells. Similarly to T cells, 4-1BB is also induced on dendritic cells (DC) following activation; however, how 4-1BB and 4-1BBL modulate DC biology is poorly understood. We provide evidence that DC express both 4-1BB and 4-1BBL upon activation with a microbial stimulus in vitro, and that these molecules interact on maturing DC. Using an in vivo DC vaccination model, we demonstrate that in the absence of 4-1BBL on the DC, there is a 2-3 fold defect in the ability of these DC to generate influenza-specific CD8 T cells in a WT host. This defect is not observed when 4-1BB-/- hosts are vaccinated with WT DC, suggesting that 4-1BBL on the DC is not acting through 4-1BB in the host, but intrinsically on the DC. Even more striking is that 4-1BB-/- DC do not show this defect in the generation of flu-specific CD8 T cells, raising the possibility of a 4-1BB-independent 4-1BBL mechanism. In that regard, we further show that anti-4-1BBL antibodies can induce Erk activation in WT DC, but not in 4-1BBL-/- DC. These results identify 4-1BBL as a DC modulator and have overall implications for vaccine design.
- Copyright © 2011 by The American Association of Immunologists, Inc.