Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor in lymphocyte activation, acting as an immune checkpoint to prevent the continued activation of T cells after an immune response and to maintain peripheral immune tolerance. PD-1 is a marker of antigen-experienced T cells. With sustained T-cell stimulation — as occurs in tumor microenvironments — PD-1 is expressed by anergic and regulatory CD4+ T cells and by exhausted CD8+ T cells. The expression of PD-1 by helper T cells is necessary for their functional interaction with B cells.1 In this issue of the Journal,2 Tuttle and colleagues report findings . . .