The coinhibitory receptor PD-1 is an important target of immunotherapy now used in the clinic, yet exactly how PD-1 inhibits T cell function remains unclear. In Science, Kamphorst et al. and Hui et al. identify the T cell costimulatory receptor CD28 as the relevant target of PD-1-mediated inhibition. The former study shows that CD28 costimulation is required for CD8+ T cell proliferation after PD-1 blockade in mice, using chronic viral infection and tumor models. Preferential proliferation of CD28+ T cells is also seen in patients receiving anti-PD-1 therapies. Hui et al. show that PD-1 is phosphorylated by the kinase Lck upon PD-L1 ligation. This interaction brings PD-1 and CD28 into proximity. Phosphorylated PD-1 specifically recruits the phosphatase Shp2, which then dephosphorylates CD28 to terminate its signaling cascade and thereby inhibit T cell proliferation. These findings lend insights into how costimulatory molecules can be manipulated to enhance or inhibit adaptive immunity.

Science (9 March 2017) doi:10.1126/science.aaf0683 & doi:10.1126/science.aaf1292