Dissecting the Role of 4-1BB and its Ligand in Enhancing CD8 Effector and Memory T Cell Responses

The Tumor necrosis factor receptor (TNFR) family member 4-1BB and its TNF family ligand, 4-1BBL, are important in modulating multiple stages of the CD8 T cell response. Here I show that during a mild influenza infection, 4-1BBL is completely dispensable for initial T cell responses, viral clearance and mouse survival. In contrast, during severe influenza infection with prolonged viral load, 4-1BB expression is sustained on lung T cells and 4-1BBL is upregulated in the lung compared to mild influenza infection. Under these conditions, 4-1BBL-deficiency results in a decreased CD8 T cell response in the lungs, higher viral load, impaired lung function and increased mortality. These findings suggest that the sustained expression of 4-1BB and its ligand as a function of viral load fine-tunes the CD8 T cell response to a level appropriate for the severity of infection. 4-1BBL is also important for maintaining CD8 memory T cell survival following the clearance of an infection. I found that 4-1BB is selectively expressed on a subset of memory CD8 T cells in the bone marrow. I further showed that the TNFR family member GITR is intrinsically required on CD8 memory T cells for 4-1BB expression in vivo, and that 4-1BB on CD8 T cells interacting with 4-1BBL on a radio-resistant cell in the bone marrow contributes to CD8 memory T cell survival. Immunotherapy with 4-1BB agonists has shown efficacy in eradication of tumors in several mouse models. These effects have been attributed to 4-1BB on multiple cell types. I found that 4-1BB either on transferred T cells or on host T cells was necessary and sufficient for inducing regression of established tumors when anti-4-1BB is combined with adoptive T cell therapy. This thesis highlights the importance of the CD8 T cell intrinsic role of 4-1BB in the immune system.Ph