The role of regulatory T cells (Treg cells) in sustaining chronic viral infection is unclear. In the Journal of Experimental Medicine, Ahmed and colleagues address this question by combining an inducible Treg cell–deletion system with the chronically infectious lymphocytic choriomeningitis virus clone 13. During chronic infection, cytotoxic T cells adopt a poorly functional 'exhausted' phenotype, but depletion of Treg cells substantially restores both functionality and proliferative potential in a costimulation-dependent manner. However, this recovery does not result in clearance of the virus, since these cytotoxic T cells still express the inhibitory molecule PD-1 and infected cells upregulate its ligand, PD-L1. A combination of PD-L1 and depletion of Treg cells effectively clears the virus and is superior to blockade of PD-L1 alone. Carefully defined depletion of Treg cells in conjunction with blockade of PD-L1 may therefore optimize the immunotherapy of chronic infection while minimizing potentially harmful side effects such as the unmasking of autoimmunity.

J. Exp. Med. (11 August 2014) 10.1084/jem.20132577