Penaloza-MacMaster, PabloKamphorst, Alice O.Wieland, AndreasAraki, KoichiIyer, Smita S.West, Erin E.O’Mara, LeighYang, ShuKonieczny, Bogumila T.Sharpe, ArleneFreeman, GordonRudensky, Alexander Y.Ahmed, Rafi2015-03-022014Penaloza-MacMaster, P., A. O. Kamphorst, A. Wieland, K. Araki, S. S. Iyer, E. E. West, L. O’Mara, et al. 2014. “Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection.” The Journal of Experimental Medicine 211 (9): 1905-1918. doi:10.1084/jem.20132577. http://dx.doi.org/10.1084/jem.20132577.0022-1007http://nrs.harvard.edu/urn-3:HUL.InstRepos:14065459Regulatory T (T reg) cells are critical for preventing autoimmunity mediated by self-reactive T cells, but their role in modulating immune responses during chronic viral infection is not well defined. To address this question and to investigate a role for T reg cells in exhaustion of virus-specific CD8 T cells, we depleted T reg cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). T reg cell ablation resulted in 10–100-fold expansion of functional LCMV-specific CD8 T cells. Rescue of exhausted CD8 T cells was dependent on cognate antigen, B7 costimulation, and conventional CD4 T cells. Despite the striking recovery of LCMV-specific CD8 T cell responses, T reg cell depletion failed to diminish viral load. Interestingly, T reg cell ablation triggered up-regulation of the molecule programmed cell death ligand-1 (PD-L1), which upon binding PD-1 on T cells delivers inhibitory signals. Increased PD-L1 expression was observed especially on LCMV-infected cells, and combining T reg cell depletion with PD-L1 blockade resulted in a significant reduction in viral titers, which was more pronounced than that upon PD-L1 blockade alone. These results suggest that T reg cells effectively maintain CD8 T cell exhaustion, but blockade of the PD-1 inhibitory pathway is critical for elimination of infected cells.en-USJournal Article2015-03-0210.1084/jem.20132577