Science https://doi.org/10.1126/science.aav7062 (2019)
The co-inhibitory receptor PD-1 is important for restraining T cell responses; however, as it is rapidly upregulated on T cells (hours after activation), it is unclear how its effects are curtailed to allow a productive response. In Science, Okazaki and colleagues find that the PD-1 ligand PD-L1 and the co-stimulatory molecule CD80 interact in cis on the surface of antigen-presenting cells. This cis interaction prevents PD-L1 from binding to its receptor PD-1 on T cells and therefore mitigates its inhibitory effects. Interestingly, the functionally closely related molecule CD86 does not demonstrate this interaction with PD-L1. Mutations in the gene encoding PD-L1 or CD80 that prevent their interaction dampen T cell activation both in vitro and in vivo in the context of cancer and autoimmune responses.