PD-L2 functions as a ligand for the inhibitory receptor PD-1; however, several studies have hinted at additional binding partners. In the Journal of Experimental Medicine, Xiao et al. show that PD-L2 also binds to the repulsive guidance molecule RGMb to mediate immunotolerance in the lung. RGMb is a glycosylphosphatidylinositol-anchored membrane protein that is known to associate via signaling receptors such as bone morphogenetic proteins and neogenin. RGMb is expressed on macrophages in the lungs and peritoneal tissues, whereas PD-L2 is expressed on dendritic cells. Blocking the RGMb–PD-L2 interaction impairs the development of respiratory tolerance, but blocking the PD-1–PD-L2 interaction does not. The molecular details of the RGMb–PD-L2 signaling complex remains to be delineated, as neither protein directly triggers downstream signaling pathways. Nevertheless, these findings provide insight into tissue-specific immunotolerance mechanisms that are mediated by PD-L2 independently of PD-1.

J. Exp. Med. (21 April 2014) doi:10.1084/jem.20130790