A checkpoint cliffhanger at the dawn of placental mammals

Abstract

The PD-1 ligands PD-L1 and PD-L2 are commonly expressed on the surface of cells, where they regulate immune system activation. However, the specific role played by each ligand has been unclear. Using site-directed mutagenesis, surface plasmon resonance, and crystallography, Philips et al. explore the distinct features of PD-L2 and identify a specific evolutionary event linked to its appearance. This work provides a deeper understanding of how the immune system adapted to mammalian placental gestation and could be an important consideration in the development of new immune checkpoint therapies.

Figure 1.

Key antigen recognition, costimulatory, and checkpoint molecules in T cell activation and tolerance. TCR signals are amplified by CD28-mediated co-stimulation. The PD-1 checkpoint antagonizes CD28-mediated costimulation to help maintain tolerance. The offsetting “elbow” and “latch” mutations in PD-L2 to maintain interactions with PD-1 are shown as red and green cartoons. It is possible this also gave PD-L2 the ability to interact with new receptors that have a role in T cell activation (see text).