Costimulatory TNFR family members in control of viral infection: Outstanding questions

• TNFR family members can have differential importance in different viral infections.
• Viral infection modulates TNF family receptors, ligands and signaling adaptors.
• The unique signals induced by each TNFR family member remain to be fully defined.
• The role of a number of TNFRs on innate cells during viral infection is poorly understood.
• Manipulation of TNFR family signaling can exacerbate or ameliorate viral disease.

Members of the TNFR family can play prominent roles in controlling the magnitude, duration and phenotype of the immune response to viruses. The importance of particular TNFRs in different viral infections and whether they contribute to viral control or pathology is dependent on the virus and the severity of the infection. TNFRs and their ligands are widely and differentially expressed on both adaptive and innate immune cell types. The cell types through which TNFRs exert their effects, the unique signals provided by each member of the family, and how these signals are ultimately integrated during an anti-viral immune response remain to be fully elucidated. Here we discuss the role of 4-1BB, OX40, CD27 and GITR and their ligands during viral infection and highlight some of the outstanding questions in the field.