Immune regulation by 4-1BB and 4-1BBL: complexities and challenges

The tumor necrosis factor receptor family member 4-1BB plays a key role in the survival of activated and memory CD8⁺ T cells. Depending on the disease model, 4-1BB can participate at different stages and influence different aspects of the immune response, likely due to the differential expression of receptor and ligand relative to other costimulatory molecules. Studies comparing mild versus severe influenza infection of mice suggest that the immune system uses inducible receptors such as 4-1BB to prolong the immune response when pathogens take longer to clear. The expression of 4-1BB on diverse cell types, evidence for bidirectional as well as receptor-independent signaling by 4-1BBL, the unexpected hyperproliferation of 4-1BB-deficient T cells, and complex effects of agonistic anti-4-1BB therapy have revealed additional roles for the 4-1BB/4-1BBL receptor/ligand pair in the immune system. In this review, we discuss these diverse roles of 4-1BB and its ligand in the immune response, exploring possible mechanisms for the observed complexities and implications for therapeutic applications of 4-1BB/4-1BBL.