Programmed cell death 1 (PD-1) is an immunosuppressive receptor that transduces an inhibitory signal into activated T cells. Although a single nucleotide polymorphism in the gene for PD-1 is associated with susceptibility to systemic lupus erythematosus, the role of PD-1 in systemic lupus erythematosus is still not well understood. In this study, we used NZB/W F1 mice, a model of lupus-like nephritis, to examine the function of PD-1 and its ligands. PD-1 was predominantly expressed on CD4+ T cells that infiltrated the kidney, and CD4+ PD-1 high T cells produced higher levels of IFN-γ than CD4+ PD-1 low or CD4+ PD-1− T cells. Stimulation with PMA/ionomycin caused splenic CD4+ PD-1+ T cells to secrete high levels of IFN-γ, IL-10, low levels of TNF-α, faint levels of IL-2, IL-21, and no IL-4, IL-17. In vivo anti–PD-1 mAb treatment reduced the number of CD4+ PD-1+ T cells in the kidney of NZB/W F1 mice and significantly reduced their mortality rate (p= 0.03). Conversely, blocking PD-L1 using an anti–PD-L1 mAb increased the number of CD4+ PD-1+ T cells in the kidney, enhanced serum IFN-γ, IL-10, and IgG2a ds-DNA–Ab levels, accelerated the nephritis, and increased the mortality rate. We conclude that CD4+ PD-1 high T cells are dysregulated IFN-γ–producing, proinflammatory cells in NZB/W F1 mice.